Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

p38 Gamma MAPK

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101521

Synonyms

Historical Background

p38 mitogen-activated protein kinases (p38 MAPKs) are a group of serine/threonine protein kinases, which together with extracellular signal-regulated kinases (ERKs) and c-Jun N-terminal kinases (JNKs) MAPKs convert upstream signals into cellular responses. Four mammalian p38 MAPK family proteins (α, β, γ, and δ) are encoded by four separate genes and play an overlapping, distinct, and even opposite role in regulating cell growth, cell death, and differentiation (Ono and Han 2000; Kumar et al. 2003; Cuenda and Rousseau 2007; Loesch and Chen 2008). Among 15 classical and nonclassical MAPKs, p38γ is an only MAPK with its C-terminus containing an unique PDZ-binding motif (Lechner et al. 1996; Li et al. 1996; Mertens et al. 1996; Cargnello and Roux 2011). p38γ signals downstream of MAPK kinase 6 (MKK6) and MKK3 (Cuenda et al. 1997; Marinissen et al. 2001), but its downstream transcription factors remain mostly unidentified as compared to p38α (Li et al. 1996; Cuenda and Rousseau 2007). p38γ is frequently activated in parallel with p38α in response to a variety of stimuli. These include stress signals (such as sorbitol (Sabio et al. 2004; Sabio et al. 2005), arsenite (Qi et al. 2007; Hou et al. 2012), radiation (Li et al. 1996; Cuenda et al. 1997; Wang et al. 2000), mitogens (Tang et al. 2005; Hou et al. 2012), cytokines, and inflammation (Cuenda et al. 1997; Risco et al. 2012; Tian et al. 2013; Yin et al. 2016) (Fig. 1).
p38 Gamma MAPK, Fig. 1

p38γ MAPK signal transduction and biological functions through cooperation with its binding-partners. p38γ is activated by phosphorylation and increased expression in response to variety of stimuli. p38γ binds several proteins by a PDZ-dependent (red arrow) and independent (blue arrow) mechanism. p38γ interaction with its partner proteins typically leads to their phosphorylation at indicated Ser and/or Thr residues and/or alterations in stability and activity as indicated. Two opposite red arrow indicate a PDZ-mediated bidirectional kinase/phosphatase complex that catalyzes both p38γ dephosphorylation and PTPH1 phosphorylation by a dynamic and microenvironment-specific mechanism. Several proteins such as Tau and p53 (a green arrow) are phosphorylated by p38γ but whether this is due to their interaction has not been demonstrated. p38γ also binds c-Jun via its C-terminal PDZ motif in cells and stimulates c-Jun transcription/AP-1 activity. Through interaction with c-Jun, ER, and/or β-catenin, p38γ may act as a key transcription coregulator to bind gene promoters and thereby directly regulate their transcription. Furthermore, p38γ activation may, through PTPH1, regulate ER and EGFR tyrosine dephosphorylation and their cellular localization. In response to inflammation, p38γ activity may play a role in stimulating pro-inflammatory cytokine expression and thereby in promoting inflammation-associated tumorigenesis and/or malignant progression. The “? ” sign indicates that involved molecules/pathways in response to p38γ activation are unclear and that biological consequences of p38γ-induced substrate phosphorylation are unknown. p38γ may directly phosphorylate and/or indirectly dephosphorylate (through PTPH1) several proteins by a dynamical /microenvironment-dependent mechanism leading to an integrated/coordinated cellular and systemic response

However, p38γ can be selectively activated under certain conditions after exposure to γ-radiation (Wang et al. 2000), cisplatin and UV (Pillaire et al. 2000), hypoxia (Conrad et al. 1999), DNA topoisomerase II inhibitors (Qi et al. 2011), antiestrogens (Qi et al. 2012), and oncogenes (Sakabe et al. 2002; Tang et al. 2005). p38γ is insensitive to p38α/p38β inhibitor SB203580 but is inhibited by pirfenidone (PFD) (Ono and Han 2000; Cuenda and Rousseau 2007; Ozes et al. 2008; Hou et al. 2012; Qi et al. 2014; Qi et al. 2015; Yin et al. 2016). Early studies showed that p38γ RNA is predominantly expressed in muscle tissues and is involved in muscle differentiation (Lechner et al. 1996; Li et al. 1996; Ono and Han 2000; Tortorella et al. 2003; Cuenda and Rousseau 2007; Perdiguero et al. 2007). Recent research found that p38γ protein is detectable in a variety of tissues (and cells), is upregulated in several types of human cancers, and promotes oncogenesis through interaction with several proteins (Loesch and Chen 2008; Hou et al. 2010a; Hou et al. 2010b; Meng et al. 2011) (Fig. 1). This review will focus on recent discoveries of new functions of p38γ MAPK through PDZ-dependent and independent interactions with its partner proteins.

p38γ Signals to and from Its Partners Through PDZ Binding

p38γ C-terminal PDZ-binding motif can mediate its specific interaction with PDZ-domain containing proteins, which may be the structural basis for p38γ-specific biological activities (Hou et al. 2010a).

PTPH1

The two-hybrid screening of human colon cDNAs showed that PDZ mediates p38γ interaction with a protein tyrosine phosphatase H1 (PTPH1) through which p38γ is dephosphorylated by PTPH1 (Hou et al. 2010b). PTPH1 is a nonmembrane tyrosine phosphatase containing a single PDZ domain (Tonks 2006). p38γ RNA and protein levels are upregulated by Ras oncogene in epithelial cells, and resultant p38γ is in turn required for Ras transforming and invasive activity (Tang et al. 2005; Qi et al. 2007; Hou et al. 2010b; Loesch et al. 2010). Further analysis showed that both K-Ras oncogene and p38γ overexpression increases PTPH1 protein expression, and the PDZ-mediated p38γ/PTPH1 interaction is required for p38γ as well as PTPH1 to potentiate K-Ras-induced transformation (Hou et al. 2010b). Although transient transfection studies showed that phosphorylated p38γ is decreased by K-Ras oncogene coexpression in rat intestinal epithelial cells (Tang et al. 2005), levels of phosphorylated p38γ proteins are increased in K-Ras mutated human colon cancer cells as compared to those without K-Ras mutation independent of PTPH1 (Hou et al. 2012). Moreover, stable expression of a dominant negative p38γ/AGF has a diminished potentiating effect on K-Ras transformation as compared to a wild-type p38γ (Hou et al. 2012), whereas stably expressed p38γ-MKK6 fusion protein blocks stress-induced death independent of phosphorylation (Qi et al. 2007). Together, these results indicate that p38γ can signal to increase K-Ras oncogenesis and/or to inhibit stress-induced cell death dependent and independent of its phosphorylation and of its substrate PTPH1 (Hou et al. 2012).

The oncogenic role of PDZ-mediated p38γ-PTPH1 complex is further supported by the fact that p38γ phosphorylates PTPH1 at S459 in vitro and in vivo, which is important for their potentiation of K-Ras transformation and antiapoptotic activities (Hou et al. 2012). Moreover, disruption of this complex by a p38γ C-terminal peptide decreases the growth of colon cancer cells (Hou et al. 2010b), and application of a specific p38γ pharmacological inhibitor pirfenidone (PFD) inhibits the malignant growth and reduces levels of p-PTPH1/S459 protein expression (Hou et al. 2012; Qi et al. 2014). Thus, PDZ-mediated p38γ-PTPH1 complex and resultant PTPH1 phosphorylation/activation plays an important role in K-Ras oncogenesis, albeit p38γ may additionally promote proliferation and/or oncogenesis independent of its own phosphorylation and/or PTPH1. Recent crystal-structure analysis of the p38γ/PTPH1 complex further suggests an essential role of p38γ in PTPH1 activity (Chen et al. 2014). In addition, phosphorylation of PTPH1 by p38γ is independent of stress-induced activation of conventional p38α and JNK pathway activities (Hou et al. 2012). Overall, PDZ-coupled p38γ/PTPH1 complex may play an important role in Ras oncogenesis through increasing cell growth and/or decreasing cell death. Because p38γ depends on its phosphorylation status to bind PTPH1, the PDZ-complex is most likely driven by p38γ phosphorylating PTPH1, rather by PTPH1 dephosphorylating of p38γ, to promote K-Ras oncogenesis (Fig. 1).

α1-Syntrophin and SAPs

Two-hybrid screening using human brain cDNA library revealed that p38γ, through its C-terminal PDZ-binding motif, binds and phosphorylates α1-syntrophin (Hasegawa et al. 1999). α1-syntrophin, a PDZ domain protein, functions as a modular adapter to recruit signaling proteins and is highly expressed in skeletal muscle (Peters et al. 1997). Although this PDZ-coupled interaction is essential for p38γ phosphorylation of α1-syntrophin, biological consequence of this interaction remains unclear (Hasegawa et al. 1999) (Fig. 1). A similar PDZ-dependent interaction was also demonstrated between p38γ and SAP90 (synapase-associated protein 90)/PSD95 (postsynaptic density protein 95) (Sabio et al. 2004) and between p38γ and SAP97 (hDlg) (Sabio et al. 2005), through which both proteins are phosphorylated with the biological consequences also unknown. Recent studies showed that the oncogenic protein β-catenin interacts with SAP97 through its PDZ motif to maintain the integrity of tight junctions (Gujral et al. 2013). Since p38γ also binds β-catenin (Yin et al. 2016), it would be interesting to explore if PDZ-coupled multiple-protein complex plays a role in maintaining epithelial polarity (Chen and Macara 2005). The interaction of SAP97/hDlg with p38γ can further regulate its interaction with polypyrimidine tract-binding protein-associated-splicing factor (PSF) and thereby causes the hDlg-RNA dissociation in stress response (Sabio et al. 2010). While these effects appear specific for p38γ and are activated in response to stress (such as sorbitol and UV radiation), cellular effects of blocking p38γ interaction with these proteins have not been demonstrated (Sabio et al. 2004; Sabio et al. 2005; Sabio et al. 2010). Since PDZ binding is a central module of scaffold proteins in maintaining barrier function (Fanning and Anderson 1999; Schlieker et al. 2004; Smock and Gierasch 2009; Monteriro et al. 2013), p38γ may play an active role in epithelial integrity through interaction with PDZ-domain containing proteins.

p38γ Binds and Activates Its Partner Proteins

In addition to PDZ-mediated interactions, p38γ can bind to other proteins by a yet unknown mechanism to impact life-important events. These interactions typically lead to its binding partner phosphorylation, stabilization, or degradation, leading to an oncogenic response. Moreover, the ability of p38γ to interact with a transcription factor will enable its recruitment to target gene promoters and thereby directly regulate gene transcription as a coactivator.

c-Jun

p38γ is required for Cot- and RhoA-induced activation of c-Jun promoter (Chiariello et al. 2000; Marinissen et al. 2001). Moreover, p38γ overexpression alone is sufficient to stimulate c-Jun promoter activity through AP-1 and MEF2 binding sites (Marinissen et al. 1999; Loesch et al. 2010). The work by Loesch et al. further showed that p38γ depends on both its C-terminal PDZ motif and phosphorylation to bind and to trans-activate c-Jun, which is essential for basal AP-1 transcription activity (Loesch et al. 2010). Further studies showed that p38γ is required for MKK6 stimulation of MMP9 promoter activity (Simon et al. 2001). Since c-Jun is positively autoregulated by its own product through AP-1 on its promoter (Angel et al. 1988), p38γ interaction with c-Jun may directly link its activity to increase AP-1 target gene expression. Indeed, c-Jun can act as a carrier to recruit p38γ onto the MMP9 and Nanog promoters, and these events are critical for p38γ-induced invasive response and cancer stem-like cell (CSC) expansion (Loesch et al. 2010; Qi et al. 2015). Since there is no PDZ domain in c-Jun protein, this interaction may not directly involve PDZ binding.

Estrogen Receptor α (ER)

p38γ interacts with the nuclear receptor ER (estrogen receptor), which plays an important role for ER to antagonize nuclear p38γ activity (Qi et al. 2006). Further, p38γ phosphorylates ER/S118 and forms a complex with ER and c-Jun on cyclin D1 promoter (Qi et al. 2012). ER requires both T311 and S118 to bind p38γ, which is important for p38γ invasive activity (Qi et al. 2006) and for p38γ increasing hormone sensitivity in breast cancer cells (Qi et al. 2012). However, PTPH1 can catalyze ER/Y537 dephosphorylation and thereby increase ER nuclear translocation and breast cancer hormonal sensitivity (Suresh et al. 2014). Although S459 is important for the PTPH1 phosphatase catalytic activity toward EGFR (epidermal growth factor receptor) (Hou et al. 2012; Ma et al. 2015), whether p38γ phosphorylates PTPH1/S459 in breast cancer has not been demonstrated. It is possible, however, that p38γ may increase breast cancer hormonal sensitivity directly by increasing p-ER/S118 levels and indirectly by decreasing p-ER/Y537 (through phosphorylating PTPH1/S459). This is because increased levels of p-ER/S118 (Kok et al. 2009) and p-ER/Y537 (Skliris et al. 2010) in clinical breast cancer are good and worse biomarkers for antiestrogen therapy, respectively. Furthermore, p38γ binds both ER and c-Jun in breast cancer cells, and treatment with tamoxifen stimulates this ternary-complex formation, which may also be critical for p38γ potentiation of breast cancer sensitivity to antiestrogens (Qi et al. 2012). In addition, p38γ is a breast cancer metastasis gene in triple-negative breast cancer (Qi et al. 2006; Meng et al. 2011; Rosenthal et al. 2011; Lee et al. 2013; Qi et al. 2015). Overall, p38γ may promote malignant progression in ER-negative breast cancer and increase hormonal sensitivity in ER-positive breast tumors.

Heat Shock Protein 90 (Hsp90)

Proteomic analysis of p38γ precipitates identified a mutant K-Ras-dependent interaction of p38γ with Hsp90 (heat shock protein 90) (Qi et al. 2014). Importantly, this complex contains mutated K-Ras protein, and p38γ protects the oncoprotein from degradation by phosphorylating Hsp90 at S595 (Qi et al. 2014). Hsp90/S595 is phosphorylated by p38γ, but not its family member p38α, which is important for stabilizing mutated (but not wild-type) K-Ras protein against proteasome-dependent degradation (Qi et al. 2014). Significantly, high levels of p38γ proteins in K-Ras mutant colon cancer cells are required to maintain the endogenous oncoprotein levels, and targeting p38γ by shRNA or pharmacological inhibitor PFD selectively inhibits K-Ras mutant colon cancer growth in vitro and/or in vivo (Qi et al. 2014). Although Hsp90 activity was previously shown to be important for K-Ras mutant cancers (Sos et al. 2009; Azoitei et al. 2012), the mutant K-Ras-specific binding of p38γ together with Hsp90 and the resultant Hsp90/S595 phosphorylation reveal a novel mechanism that can be explored for targeting mutant K-Ras protein.

DNA Topoisomerase IIα (Topo IIα)

Topo IIα is an important therapeutic target for cancer chemotherapy, and application of Topo II inhibitors (such as Adriamycin: ADR; etoposide: VP16) is a standard therapeutic strategy for many types of human cancer (Chen and Liu 1994). However, determinants for therapeutic response to Topo II drugs are largely unknown (Pritchard et al. 2008). Studies showed that treatment of breast cancer cells with Topo II inhibitors, but not with the antimicrotubule drug taxol, increases p38γ (but not p38α) phosphorylation, which is associated with increased sensitivity of breast cancer cells to Topo II drugs (Qi et al. 2011). Topo IIα is a nuclear protein (Chen and Liu 1994), and in contrast to p38α, phosphorylated p38γ is also mostly accumulated in the nucleus (Qi et al. 2007; Sabio et al. 2010). These findings suggest that p38γ activation may be required for the positive feedback loop between Topo II and its inhibitors, through which p38γ phosphorylates and thereby activates Topo II to increase its therapeutic target activity. Indeed, p38γ binds, phosphorylates Topo IIα/S1542, and increases the Topo II catalytic activity (Qi et al. 2011). In addition, p38γ increases Topo IIα protein stability dependent of phosphorylation, and elevated p38γ expression in breast cancer specimens correlates with increased Topo IIα levels (Qi et al. 2011). Furthermore, Ras oncogene stimulates Topo IIα (Chen et al. 1999) and p38γ expression (Tang et al. 2005), and transformed cells are more sensitive to the Topo II inhibitor VP-16 as compared to their nontransformed counterparts (Chen et al. 1997). These results together indicate that increased p38γ expression in malignant cells may be a good marker for their sensitivity to Topo II inhibitors.

β-Catenin

β-catenin is a central component of Wnt signaling and plays a critical role in colon cancer development and progression by stimulating Wnt transcription activity (Clevers 2006). Conditional p38γ knockout from intestinal epithelial cells (IECs) decreases β-catenin expression, inhibits Wnt activity, and attenuates colon tumorigenesis in an azoxymethane(AOM)/dextran sodium sulfate (DSS) mouse model (Yin et al. 2016). Further analysis showed that p38γ binds β-catenin and increases its protein stability by stimulating its S605 phosphorylation and thereby decreasing its proteasome-dependent degradation (Yin et al. 2016). Moreover, inflammation stimulates p38γ and β-catenin phosphorylation, and β-catenin/S605 is required for p38γ stimulating of Wnt transcriptional activity and for colon cancer growth (Yin et al. 2016). The role of p38γ-phosphorylating β-catenin/S605 in p38γ promoting K-Ras oncogenesis and inflammation-induced colon cancer, however, remains to be explored further.

p38γ Phosphorylates Other Proteins

Studies also found that p38γ can phosphorylate Tau and p53 proteins. Although this may result from their interactions, experimental evidence has not been demonstrated.

Tau

Tau is a microtubule-associated protein that is hyperphosphorylated in Alzheimer’s disease. Studies showed that p38γ and its family member p38δ can directly phosphorylate Tau at several serine and threonine residues (Goedert et al. 1997). Moreover, p38γ appears to be the most potent MAPK to phosphorylate Tau in intact cells as compared to its family proteins (Buee-Scherrer and Goedert 2002). However, biological consequences of tau phosphorylation by p38γ remain unknown.

p53

p38γ and p38α also phosphorylate the tumor suppressor p53 at Ser33 (Kwong et al. 2009). Although p38γ is required for Ras-induced senescence as well as induction of p21 (a p53 target) in fibroblasts, whether p53/S33 phosphorylation by p38γ plays a role in this process is unclear (Kwong et al. 2009).

p38γ Promotes Pro-Inflammatory Reactions

p38 MAPKs are activated by inflammation and regulate expression of cytokines, inflammatory mediators, and survival genes (Kumar et al. 2003). Among the 4 family proteins, p38γ and p38α are frequently coactivated in response to inflammation (Abdollahi et al. 2003; Korb et al. 2006; Long and Loeser 2010; Tian et al. 2013). Experiments with IEC-specific p38α knockout showed that p38α is inhibitory to inflammation-induced colon tumorigenesis (Otsuka et al. 2010; Wakeman et al. 2012; Gupta et al. 2014). On the contrary, studies with a whole body (Del Reino et al. 2014) and IEC-specific p38γ knockout (Yin et al. 2016) demonstrated a promoting role of p38γ in colon cancer development in the AOM/DSS inflammation mouse model. The required role of p38γ in inflammation-induced tumorigenesis was further demonstrated in a mouse skin cancer model (Zur et al. 2015). Critically, a systemic application of the p38γ inhibitor PFD only blocks the AOM/DSS induced pro-inflammatory cytokine expression and colon-tumorigenesis in wild-type, but not IEC-specific p38γ knockout, mice (Yin et al. 2016). In addition, one recent study showed that neutrophils in myeloid-specific compound p38γ and p38δ double knockout mice are deficient in migration and infiltration in response to the liver metabolism reprograming (Gonzalez-Teran et al. 2016). These results together indicate a critical role of p38γ in inflammation and in inflammation-induced tumorigenesis.

Mechanisms by which p38γ is required for inflammation-induced tumorigenesis are multiple and may be tissue-, cell-, and even stage-specific. p38γ is activated in cells in response to TNF (Cuenda et al. 1997) and is also required for TNF and IL-1 induced activation of NF-kB (Tian et al. 2013). Further, levels of pro-inflammatory cytokines (IL-6, IL-1β, and TNF) are decreased in bone-marrow macrophages derived from whole body p38γ knockout mice after LPS (Risco et al. 2012) and in intestinal tissues of IEC-specific p38γ knockout mice in response to DSS (Yin et al. 2016). Also, treatment of mice with the inflammation stimulus DSS specifically activate p38γ, but not p38α, together with activation of IL-1β, IL-6, and TNF (Yin et al. 2016), and treatment with IL-1β activates both p38α and p38γ in chondrocytes (Long and Loeser 2010). These results indicate an integrated role of p38γ and p38α in feedback loops of pro-inflammatory cytokine signaling. Furthermore, treatment of mice with the p38γ inhibitor PFD reduces TNF-induced shock and decreases IL-6 expression (Cain et al. 1998) and T cell activation (Visner et al. 2009). These results together suggest that p38γ may be important for pro-inflammatory cytokine expression and/or secretion and may collaborate with p38α in fine-tuning coordinated inflammatory response. Targeting p38γ with PFD may have application potentials in prevention of inflammation-induced tumorigenesis.

Other properties of p38γ may also contribute its pro-inflammatory activity. At cellular levels, p38γ is proliferative and/or antiapoptotic (Qi et al. 2007; Loesch et al. 2010; Wu et al. 2010; Kukkonen-Macchi et al. 2011; Hou et al. 2012). Moreover, p38γ is invasive and metastatic (Qi et al. 2006; Loesch et al. 2010; Meng et al. 2011; Rosenthal et al. 2011) and increases CSC expansion (Qi et al. 2015). Furthermore, p38γ promotes differentiation in fibroblasts (Lechner et al. 1996; Gillespie et al. 2009; Zhang et al. 2011) and facilitates glucose transport (Ho et al. 2003), metabolic adaption (Pogozelski et al. 2009), and cell-cycle progression through G2/M phase (Wang et al. 2000). These properties may play a critical role for p38γ pro-inflammatory activity. It should be noted that p38α is a tumor suppressor (Chen et al. 2000; Bulavin and Fornace 2004; Qi et al. 2004; Dolado et al. 2007; Kennedy et al. 2007) and antagonizes p38γ activity (Qi et al. 2007; Loesch and Chen 2008; Lassar 2009). Because p38α and p38γ are coactivated in response to inflammation (Abdollahi et al. 2003; Korb et al. 2006; Long and Loeser 2010; Tian et al. 2013), the resultant p38γ/p38α activity ratio may determine if the integrated response is pro-inflammatory versus anti-inflammatory.

Summary

Studies showed several specific properties of p38γ MAPK. Structurally, p38γ is a nonclassical p38 MAPK family member and is the only MAPK that has a unique C-terminal PDZ-binding motif (Cuenda and Rousseau 2007; Hou et al. 2010a). In response to stimuli, p38γ is activated both by elevated RNA and/or protein expression and by increased phosphorylation (Cuenda et al. 1997; Boppart et al. 2000; Chiariello et al. 2000; Franco et al. 2002; Tang et al. 2005; Qi et al. 2006; Qi et al. 2007; Ding et al. 2009; Pogozelski et al. 2009; Qi et al. 2011; Hou et al. 2012; Qi et al. 2012). This property may enable p38γ to have a sustained effect in various biological responses. Furthermore, p38γ is the only MAPK so far that has its own specific phosphatase PTPH1 through PDZ binding (Hou et al. 2010b). This complex may promote K-Ras oncogenesis through a dynamic p38γ-induced PTPH1 phosphorylation and PTPH1-induced p38γ dephosphorylation by a time-, site-, and microenvironment-specific mechanism (Hou et al. 2010b; Hou et al. 2012; Kolch et al. 2015). Although p38γ can signal through several substrates and/or partners, it may only need some of them to trigger a proliferative and/or pro-inflammatory response and to promote inflammation-induced oncogenesis through their integrated activities (Fig. 1). It is important to mention that the p38γ-specific pharmacological inhibitor PFD would be a potent tool for further verification of systemic p38γ activities (Ozes et al. 2008; Moran 2011; Qi et al. 2014; Qi et al. 2015; Yin et al. 2016). Most importantly, PFD is nontoxic and PDA-approved for the treatment of lung fibrosis in clinic (Noble et al. 2011; Richeldi et al. 2011; Schaefer et al. 2011; King et al. 2014). Targeting p38γ by PFD may be a novel strategy for prevention and treatment of inflammation-induced cancer.

Notes

Acknowledgements

The work in Chen lab was supported by grants from National Institutes of Health, Department of Veterans Affair (VA), and Department of Defense (DoD). We would like to acknowledge the former lab members Drs. Jung Tang, Rocky Pramanik, Song-Wang Hou, Mathew Loesch, Adrienne Lepp, Padmanaban S. Suresh, Shao Ma, and Ning Yin for their contributions.

References

  1. Abdollahi T, Robertson NM, Abdollahi A, Litwack G. Inhibition of TRAIL-induced apoptosis by IL-8 is mediated by the p38-MAPK pathway in OVCAR3 cells. Apoptosis. 2003;10:1383–93.CrossRefGoogle Scholar
  2. Angel P, Hattori K, Smeal T, Karin M. The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. Cell. 1988;55:875–85.PubMedCrossRefGoogle Scholar
  3. Azoitei N, Hoffmann CM, Ellegast JM, Ball CR, Obermayer K. GoBele Uea. Targeting of KRAS mutant tumors by HSP90 inhibitors involves degradation of STK33. J Exp Med. 2012;209:697–711.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Boppart MD, Asp S, Wojtaszewski JF, Fielding RA, Mohr T, Goodyear LJ. Marathon running transiently increases c-Jun NH2-terminal kinase and p38 activities in human skeletal muscle. J Physiol. 2000;526:663–39.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Buee-Scherrer V, Goedert M. Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells. FEBS Lett. 2002;515:151–4.PubMedCrossRefGoogle Scholar
  6. Bulavin DV, Fornace AJ. p38 MAP kinase’s emerging role as a tumor suppressor. Adv Cancer Res. 2004;92:95–118.PubMedCrossRefGoogle Scholar
  7. Cain WC, Stuart RW, Lefkowitz DL, Starnes JD, Margolin S, Lefkowitz SS. Inhibition of tumor necrosis factor and subsequent endotoxin shock by pirfenidone. Int J Immunopharmacol. 1998;20:685–95.PubMedCrossRefGoogle Scholar
  8. Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011;75:50–83.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Chen AY, Liu LF. DNA topoisomerases: essential enzymes and lethal targets. Annu Rev Pharmacol Toxicol. 1994;34:191–218.PubMedCrossRefGoogle Scholar
  10. Chen X, Macara IG. Par-3 controls tight junction assembly through the Rac exchange factor Tiam1. Nat Cell Biol. 2005;7:262–9.PubMedCrossRefGoogle Scholar
  11. Chen G, Shu J, Stacey DW. Oncogenic transformation potentiates apoptosis induction, S-phase arrest and WAF1 induction by etoposide. Oncogene. 1997;15:1643–51.PubMedCrossRefGoogle Scholar
  12. Chen G, Templeton D, Suttle DP, Stacey D. Ras stimulates DNA topoisomerase IIα through MEK: a link between oncogenic signaling and a therapeutic target. Oncogene. 1999;18:7149–60.PubMedCrossRefGoogle Scholar
  13. Chen G, Hitomi M, Han J, Stacey DW. The p38 pathway provides negative feedback to Ras proliferative signaling. J Biol Chem. 2000;275:38973–80.PubMedCrossRefGoogle Scholar
  14. Chen K, Lin S, Wu M, Ho M, Santhanam A, Chou C, et al. Reciprocal allosteric regulation of p38γ and PTPN3 involves a PDZ domain-modulated complex formation. Sci Signal. 2014;7:ra98.PubMedCrossRefGoogle Scholar
  15. Chiariello M, Marinissen MJ, Gutkind JS. Multiple mitogen-activated protein kinase signaling pathways connect the Cot oncoprotein to the c-jun promoter and to cellular transformation. Mol Cell Biol. 2000;20:1747–58.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Clevers H. Wnt/β-catenin signaling in development and disease. Cell. 2006;127:469–80.PubMedCrossRefGoogle Scholar
  17. Conrad PW, Rust RT, Han J, Millhorn DE, Beitner-Johnson D. Selective activation of p38α and p38γ by hopoxia. Role in regulation of cyclin D1 by hypoxia in PC12 cells. J Biol Chem. 1999;274:23570–6.PubMedCrossRefGoogle Scholar
  18. Cuenda A, Rousseau S. p38 MAP-Kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta. 2007;1773:1358–75.PubMedCrossRefGoogle Scholar
  19. Cuenda A, Cohen P, Buee-Scherrer V, Goedert M. Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). EMBO J. 1997;16:295–305.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Del Reino P, Alsina-Beauchamp D, Escos A, Cerezo-Guisado MI, Risco A, Aparicio N. Pro-oncogenic role of alternative p38 mitogen-activated protein kinases p38γ and p38δ, linking inflammation and cancer in colitis-associated colon cancer. Cancer Res. 2014;74:6150–60.PubMedCrossRefGoogle Scholar
  21. Ding H, Gabali AM, Jenson SD, Lim MS, Elenitoba-Johnson KSJ. p38 mitogen activated protein kinase expression and regulation by interleukin-4 in human B cell non-Hodgkin lymphomas. J Hematop. 2009;2:195–204.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Dolado I, Swat A, Ajenjo N, De Vita G, Cuadrado A, Nebreda AR. p38α MAP kinase as a sensor of reactive oxygen species in tumorigenesis. Cancer Cell. 2007;11:191–205.PubMedCrossRefGoogle Scholar
  23. Fanning AS, Anderson JM. PDZ domains: fundamental building blocks in the organization of protein complexes at the plasma membrane. J Clin Invest. 1999;103:767–72.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Franco DL, Nojek IM, Molinero L, Coso OA, Costas MA. Osmotic stress sensitizes naturally resistant cells to TNF-α-induced apoptosis. Cell Death Differ. 2002;9:1090–8.PubMedCrossRefGoogle Scholar
  25. Gillespie MA, Grand FL, Scime A, Kuang S, von Maltzahn J, Seale V, et al. p38γ-dependent gene silencing restricts entry into the myogenic differentiation program. J Cell Biol. 2009;187:991–1005.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Goedert M, Hasegawa M, Jakes R, Lawler S, Cuenda A, Cohen P. Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. FEBS Lett. 1997;409:57–62.PubMedCrossRefGoogle Scholar
  27. Gonzalez-Teran B, Matesanz N, Nikolic I, Verdugo MA, Sreeramkumar V. Hernandez-Cosido Lea. p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration. EMBO J. 2016;35:536–52.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Gujral TS, Karp ES, Chan M, Chang BH, MacBeath G. Family-wide investigation of PDZ domain-mediated protein-protein interactions implicates β-catenin in maintaining the integrity of tight junction. Chem Biol. 2013;20:816–27.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Gupta J, Barantes IB, Igea A, Sakellariou S, Pateras I, Gorgoulis VG. Dual function of p38α MAPK in colon cancer: suppression of colities-associated tumor initiation but requirement for cancer cell survival. Cancer Cell. 2014;25:484–550.PubMedCrossRefGoogle Scholar
  30. Hasegawa M, Cuenda A, Spillantini MG, Thomas GM, Buee-Scherrer V, Cohen P, et al. Stress-activated protein kinase-3 interacts with the PDZ domain of α1-syntrophin: a mechanism for specific substrate recognition. J Biol Chem. 1999;274:12626–31.PubMedCrossRefGoogle Scholar
  31. Ho RC, Alcazar O, Fujii N, Hirshman MF, Goodyear LJ. p38γ MAPK regulation of glucose transporter expression and glucose uptake in Ly myotubes and mouse skeletal muscle. Am J Phys Regul Integr Comp Phys. 2003;286:R342–R9.Google Scholar
  32. Hou S, Lepp A, Chen G. p38 gamma MAP kinase. UCSD-Nature Molecular Pages. 2010a; doi: 10.1038/mp.a001720.01.Google Scholar
  33. Hou SW, Zhi H, Pohl N, Loesch M, Qi X, Li R, et al. PTPH1 dephosphorylates and cooperates with p38γ MAPK to increases Ras oncogenesis through PDZ-mediated interaction. Cancer Res. 2010b;70:2901–10.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Hou S, Padmanaban S, Qi X, Leep A, Mirza S, Chen G. p38g MAPK signals through phosphorylating its phosphatase PTPH1 in regulating Ras oncogenesis and stress response. J Biol Chem. 2012;287:27895–905.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Kennedy NJ, Cellurale C, Davis RJ. A radical role for p38 MAPK in tumor initiation. Cancer Cell. 2007;11:101–3.PubMedCrossRefGoogle Scholar
  36. King TE, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083–92.PubMedCrossRefGoogle Scholar
  37. Kok M, Holm-Wigerup C, Hauptmann M, Michalides R, Stal O, Linn S, et al. Estrogen receptor-α phosphorylation at serine-118 and tamoxifen response in breast cancer. J Natl Cancer Inst. 2009;101:1725–9.PubMedCrossRefGoogle Scholar
  38. Kolch W, Halasz M, Granovskaya M. N. KB. The dynamic control of signal transduction networks in cancer cells. Nat Rev Cancer. 2015;15:515–27.PubMedCrossRefGoogle Scholar
  39. Korb A, Tohidast-Akrad M, Cetin E, Axmann R, Smolen J, Schett G. Differential tissue expression and activation of p38 MAPK α, β, γ, and δ isoforms in rheumatoid arthritis. Arthritis Rheum. 2006;54:2745–56.PubMedCrossRefGoogle Scholar
  40. Kukkonen-Macchi A, Sicora O, Kaczynska K, Oetken-Lindholm C, Pouwels J, Laine L, et al. Loss of p38γ MAPK induces pleitropic mitotic defects and massive cell death. J Cell Sci. 2011;124:216–27.PubMedCrossRefGoogle Scholar
  41. Kumar S, Boehm J, Lee JC. p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov. 2003;2:717–26.PubMedCrossRefGoogle Scholar
  42. Kwong J, Hong L, Liao R, Deng Q, Han J, Sun P. p38α and p38γ mediates oncogenic ras-induced senescence through different mechanisms. J Biol Chem. 2009;284:11237–46.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Lassar AB. The p38 MAPK family, a pushmi-pullyu of skeletal muscle differentiation. J Cell Biol. 2009;187:941–3.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Lechner C, Zahalka MA, Giot J, Moller NP, Ullrich A. ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc Natl Acad Sci. 1996;93:4355–9.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Lee ST, Feng M, Wei Y, Li Y, Guan P, Jiang X, et al. Protein tyrosine phosphatase UBASH3B is overexpressed in triple-negative breast cancer and promotes invasion and metastasis. Proc Natl Asso Sci USA. 2013;110:11121–6.CrossRefGoogle Scholar
  46. Li Z, Jiang Y, Ulevitch RJ, Han J. The primary structure of p38γ: a new member of p38 group of MAP kinases. Biochem Biophys Res Commun. 1996;228:334–40.PubMedCrossRefGoogle Scholar
  47. Loesch M, Chen G. The p38 MAPK stress pathway as a tumor suppressor or more? Front Biosci. 2008;13:3581–93.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Loesch M, Zhi H, Hou S, Qi X, Li R, Basir Z, et al. p38γ MAPK cooperates with c-Jun in trans-activating matrix metalloproteinase 9. J Biol Chem. 2010;285:15149–58.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Long DL, Loeser RF. p38g mitogen-activated protein kinase suppresses chondrocyte production of MMP-13 in response to catabolic stimulation. Osteoarthr Cartil. 2010;18:1203–10.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Ma S, Yin N, Qi X, Pfister SL, Zhang M, Ma R, et al. Tyrosine dephosphorylation enhances the therapeutic target activity of epidermal growth factor receptor (EGFR) by disrupting its interaction with estrogen receptor (ER). Oncotarget. 2015;6:13320–33.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Marinissen MJ, Chiariello M, Pallante M, Gutkind JS. A network of mitogen-activated protein kinases links G protein-coupled receptors to the c-jun promoter: a role for c-Jun NH2-terminal kinase, p38s, and extracellular signal-regulated kinase 5. Mol Cell Biol. 1999;19:4289–301.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Marinissen MJ, Chiariello M, Gutkind JS. Regulation of gene expression by the small GTPase Rho through the ERK6 (p38γ) MAP kinase pathway. Genes Dev. 2001;15:535–53.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Meng F, Zhang H, Liu G, Kreike B, Chen W, Sethi S, et al. p38γ mitogen-activated protein kinase contributes to oncogenic properties maintenance and resistance to poly (ADP-ribose)-polymerase-1 inhibition in breast cancer. Neoplasia. 2011;13:472–82.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Mertens S, Craxton M, Goedert M. SAP kinase-3, a new member of the family of mammalian stress-activated protein kinases. FEBS Lett. 1996;383:273–6.PubMedCrossRefGoogle Scholar
  55. Monteriro AC, Sumagin R, Rankin CR, Leoni G, Mina MJ, Reiter DM. JAM-A associates with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and regulate epithelial barrier function. Mol Biol Cell. 2013;24:2849–60.CrossRefGoogle Scholar
  56. Moran N. p38 kinase inhibitor approved for idiopathic pulmonary fibrosis. Nat Biotechnol. 2011;29:301.PubMedCrossRefGoogle Scholar
  57. Noble PW, Albera C, Bradford W, Costabel U, Glassberg MK, Kardatzke D, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377:1760–9.PubMedCrossRefGoogle Scholar
  58. Ono K, Han J. The p38 signal transduction pathway activation and function. Cell Signal. 2000;12:1–13.PubMedCrossRefGoogle Scholar
  59. Otsuka M, Kang YJ, Ren J, Jiang H, Wang Y, Omata M, et al. Distinct effects of p38α deletion in myeloid lineage and gut epithelia in mouse models of inflammatory bowel disease. Gastroenterology. 2010;138:1255–65.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Ozes O, Blatt LM, Seiwert SD. Use of pirfenidone in therapeutic regimens. United States Patent-US 7,407,973 B2. 2008;Aug. 5th:1–46.Google Scholar
  61. Perdiguero E, Ruiz-Bonilla V, Gresh L, Hui L, Ballestar E, Sousa-Victor P, et al. Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38α in abrogating myoblast proliferation. EMBO J. 2007;26:1245–56.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Peters MF, Adams ME, Froehner SC. Differential association of syntrophin pairs with the dystrophin complex. J Cell Biol. 1997;138:81–93.PubMedPubMedCentralCrossRefGoogle Scholar
  63. Pillaire M, Nebreda AR, Darbon J. Cisplatin and UV radiation induce activation of the stress-activated protein kinase p38γ in human melanoma cells. Biochem Biophys Res Commun. 2000;278:724–8.PubMedCrossRefGoogle Scholar
  64. Pogozelski A, Geng T, Li P, Lira V, Zhang M, Chi JT, et al. p38γ mitogen-activated protein kinase is a key regulator in skeletal muscle metabolic adaptation in mice. PLoS One. 2009;4:e7934.PubMedPubMedCentralCrossRefGoogle Scholar
  65. Pritchard KI, Messersmith H, Elavathil L, Trudeau M, O’Malley F, DhesyThind B. HER-2 and topoisomerase II as predictors of response to chemotherapy. J Clin Oncol. 2008;26:736–44.PubMedCrossRefGoogle Scholar
  66. Qi X, Tang J, Pramanik R, Schultz RM, Shirasawa S, Sasazuki T, et al. p38 MAPK activation selectively induces cell death in K-ras mutated human colon cancer cells through regulation of vitamin D receptor. J Biol Chem. 2004;279:22138–44.PubMedCrossRefGoogle Scholar
  67. Qi X, Tang J, Loesch M, Pohl N, Alkan S, Chen G. p38γ MAPK integrates signaling cross-talk between Ras and estrogen receptor to increase breast cancer invasion. Cancer Res. 2006;66:7540–7.PubMedPubMedCentralCrossRefGoogle Scholar
  68. Qi X, Pohl NM, Loesch M, Hou S, Li R, Qin JZ, et al. p38α antagonizes p38γ activity through c-Jun-dependent ubiquitin-proteasome pathways in regulating Ras transformation and stress response. J Biol Chem. 2007;282:31398–408.PubMedCrossRefGoogle Scholar
  69. Qi X, Hou S, Lepp A, Li R, Basir Z, Lou Z, et al. Phosphorylation and stabilization of topoisomerase IIα by p38γ MAPK sensitize breast cancer cells to its poisons. J Biol Chem. 2011;286:35883–90.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Qi X, Zhi H, Lepp A, Wang P, Huang J, Basir Z, et al. p38γ mitogen-activated protein kinase (MAPK) confers breast cancer hormone sensitivity by switching estrogen receptor (ER) signaling from classical to nonclassical pathway via stimulating ER phosphorylation and c-Jun transcription. J Biol Chem. 2012;287:14681–91.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Qi XM, Xie C, Hou S, Li G, Yin N, Dong L, et al. Identification of a ternary protein-complex as a therapeutic target for K-Ras-dependent colon cancer. Oncotarget. 2014;5:4269–82.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Qi XM, Yin N, Ma S, Lepp A, Tang J, Jing W. p38γ MAPK is a therapeutic target for triple-negative breast cancer by stimulation of cancer stem-like cell expansion. Stem Cells. 2015;33:2738–47.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Richeldi L, Yasothan U, Kirkpatrick DS. Pirfenidone. Nat Rev Drug Discov. 2011;10:489–90.PubMedCrossRefGoogle Scholar
  74. Risco A, Fresno C, Mambol A, Alsina-Beauchamp D, MacKenzie KF, Yang HA. p38γ and p38δ kinases regulate the toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation. Proc Natl Acad Sci U S A. 2012;109:11200–5.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Rosenthal DT, Lyer H, Escudero S, Bao L, Wu Z, Ventura AC, et al. p38γ promotes breast cancer motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior. Cancer Res. 2011;71:6338–49.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Sabio G, Reuver S, Feijoo C, Hasegawa M, Thomas GM, Centeno F, et al. Stress- and mitogen-induced phosphorylation of the synapse-associated protein SAP90/PSD-95 by activation of SAPK3/p38γ and ERK1/ERK2. Biochem J. 2004;380:19–30.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Sabio G, Simon J, Arthur C, Kuma Y, Peggie M, Carr J, et al. p38γ regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP. EMBO J. 2005;24:1134–45.PubMedPubMedCentralCrossRefGoogle Scholar
  78. Sabio G, Cerezo-Guisado MI, Reino P, Inesta-Vaquera FA, Rousseau S, Arthur JSC, et al. p38γ regulates interactin of nuclear PSF and RNA with the tumor-suppressor hDlg in response to osmotic shock. J Cell Sci. 2010;123:2596–604.PubMedPubMedCentralCrossRefGoogle Scholar
  79. Sakabe K, Teramoto H, Zohar M, Behbahani B, Miyazaki H, Chikumi H, et al. Potent transforming activity of the small GTP-binding protein Rit in NIH 3T3 cells: evidence for a role of a p38γ-dependent signaling pathway. FEBS Lett. 2002;511:15–20.PubMedCrossRefGoogle Scholar
  80. Schaefer CJ, Ruhrmund DW, Pan L, Selwert SD, Kossen K. Antifibrotic activities of pirfenidone in animal models. Eur Respir Rev. 2011;20:85–97.PubMedCrossRefGoogle Scholar
  81. Schlieker C, Mogk A, Bukau B. A PDZ switch for a cellular stress response. Cell. 2004;117:417–20.PubMedCrossRefGoogle Scholar
  82. Simon C, Simon M, Vucelic G, Hicks MJ, Plinkert PK, Koitchev A, et al. The p38 SAPK pathway regulates the expression of the MMP-9 collagenase via AP-1-dependent promoter activation. Exp Cell Res. 2001;271:344–55.PubMedCrossRefGoogle Scholar
  83. Skliris GP, Nugent Z, Watson PH, Murphy LC. Estrogen receptor alpha phosphorylated at tyrosine 537 is associated with poor clinical outcome in breast cancer patients treated with tamoxifen. Horm Canc. 2010;1:215–21.CrossRefGoogle Scholar
  84. Smock R, Gierasch LM. Sending signals dynamically. Science. 2009;324:198–203.PubMedPubMedCentralCrossRefGoogle Scholar
  85. Sos M, Michel K, Zander T, Weiss J, Frommolt P, Peifer M, et al. Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions. J Clin Invest. 2009;119:1727–40.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Suresh PS, Ma S, Migliaccio A, Chen G. Protein-tyrosine phosphatase H1 increases breast cancer sensitivity to antiestrogens by dephosphorylating estrogen receptor at tyr537. Mol Cancer Ther. 2014;13:230–8.PubMedCrossRefGoogle Scholar
  87. Tang J, Qi X, Mercola D, Han J, Chen G. Essential role of p38γ in K-Ras transformation independent of phosphorylation. J Biol Chem. 2005;280:23910–7.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Tian Y, Yuan W, Fujita N, Wang J, Wang H, Shapiro IM, et al. Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-κB. Am J Pathol. 2013;182:2310–21.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Tonks NK. Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev Mol Cell Biol. 2006;7:833–46.PubMedCrossRefGoogle Scholar
  90. Tortorella LL, Lin CB, Pilch PF. ERK6 is expressed in a developmentally regulated manner in rodent skeletal muscle. Biochem Biophys Res Commun. 2003;306:163–8.PubMedCrossRefGoogle Scholar
  91. Visner GA, Liu F, Bizargity P, Liu H, Liu K, Yang J, et al. Pirfenidone inhibits T cell activation, proliferation, cytokine and chemokine production, and host alloresponses. Transplantation. 2009;88:330–8.PubMedPubMedCentralCrossRefGoogle Scholar
  92. Wakeman D, Schneider JE, Liu J, Wandu WS, Erwin CR, Guo J, et al. Deletion of p38-alpha mitogen-activated protein kinase within the intestinal epithelium promotes colon tumorigenesis. Surgery. 2012;152:286–93.PubMedPubMedCentralCrossRefGoogle Scholar
  93. Wang X, McGowan CH, Zhao M, He L, Downey JS, Fearns C, et al. Involvement of the MKK6-p38γ cascade in γ-radiation-induced cell cycle arrest. Mol Cell Biol. 2000;20:4543–52.PubMedPubMedCentralCrossRefGoogle Scholar
  94. Wu CC, Wu X, Han J, Sun P. p38g regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage. Protein Cell. 2010;1:573–83.PubMedPubMedCentralCrossRefGoogle Scholar
  95. Yin N, Qi X, Tsai S, Lu Y, Basir Z, Oshima K. p38γ MAPK is required for inflammation-associated colon tumorigenesis. Oncogene. 2016;35:1039–48.PubMedCrossRefGoogle Scholar
  96. Zhang J, Harrison JS, Studzinski GP. Isoforms of p38MAPK gamma and delta contribute to differentiation of human AML cells induced by 1,25-dihydroxyvitamin D3. Exp Cell Res. 2011;317:117–30.PubMedCrossRefGoogle Scholar
  97. Zur R, Garcia-Ibanez L, Nunez-Buiza A, Aparicio N, Liappas G, Escos A. Combined deletion of p38γ and p38δ reduces skin inflammation and protects from carcinogenesis. Oncotarget. 2015;6:12920–35.PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Pharmacology and Toxicology, Zablocki Department of Veterans Affairs Medical CenterMedical College of WisconsinMilwaukeeUSA