CD151 antigen; CD151 antigen (Raph blood group); GP27; Hemidesmosomal tetraspanin CD151; Membrane glycoprotein SFA-1; MER2; PETA-3; Platelet endothelial tetraspan antigen-3; Platelet surface glycoprotein gp27; Platelet-endothelial cell tetraspan antigen 3; Platelet-endothelial tetraspan antigen 3; RAPH; Tetraspanin-24; TSPAN24; Tspan-24
CD151 also known as GP-27/MER-2/PETA-3/RAPH/SFA-1/TSPAN-24 belongs to tetraspanin superfamily. It is a plasma membrane protein which forms a “tetraspanin web” and a stable laminin-binding complex with integrins α3β1: α6β1 and α3β1:α6β4 in kidney and skin (Sterk et al. 2002). It acts as a membrane receptor, forms tetraspanin-enriched microdomains (TEMs) which serve as molecular facilitator (Zoller 2009), involved in intracellular signaling (Yauch et al. 1998). It plays vital role in cell proliferation and death (Zhang et al. 2001). It is associated with differential neural development and cognitive function, and it is essential for the proper organization of kidney, skin, and inner ear and involved in erythropoiesis and protects against pulmonary fibrosis (Armoskus et al. 2014).
CD151 Structure and Localization
Universal Role of CD151 in Signaling
The cardinal role of CD151 includes conservation of epithelial cell integrity, platelet aggregation, control membrane fusion, wound healing, trafficking, cell motility, angiogenesis, and tumor metastasis. It is normally expressed on endothelial cells and overexpressed in cancer cells where it is associated with cancer progression and metastasis (Yoo et al. 2011).
CD151 as a Versatile Hemidesmosomal Linker Protein
CD151 is expressed by various epithelia and mesenchymal cells. Basal epithelial cells are connected to the extracellular matrix at an anchoring junction by hemidesmosomes. Skin is a complex epithelial which contains hemidesmosomes composed of transmembrane proteins like α6β4 integrin, CD151, and cytoplasmic proteins like BPAG1e and plectin. CD151 is predominantly associated with α6β4 in hemidesmosomes, whereas it is partially codistributed with α3β1 in focal adhesions (Chaudhari and Vaidya 2015). Recent reports indicate that these hemidesmosomal linker proteins play a role in various cellular processes like cell motility and cytoskeleton dynamics apart from their known anchoring function (Sterk et al. 2000). The expression of α6β4 in the pre-hemidesmosomal clusters is associated with upregulation of CD151, which is due to increased cell surface expression. CD151 is the only tetraspanin associated with hemidesmosomal structures and thus a major component of (pre)-hemidesmosomal structures, and its recruitment into hemidesmosomes is regulated by the integrin α6β4. CD151 plays a role in the formation and stability of hemidesmosomes by providing a framework for the spatial organization of the different hemidesmosomal components. Others, such as CD9 and CD81, remain diffusely distributed at the cell surface.
Role of CD151 in Cancer Metastasis
Adhesion-dependent activation of endothelial cells caused diminished expression of signaling pathways of angiogenesis and cytoskeleton reorganization. CD151 regulates cytoskeletal reorganization, invasion, and cell adhesion functions of endothelial cells during pathological angiogenesis by modulating laminin-binding integrins-mediated activation of PI3K/Akt, JNK, and PKC pathways. CD151 ablation was found to be associated with impaired pathological angiogenesis without vascular defect during normal development. Platelet-enhanced ECFC angiogenesis requires platelet tetraspanin CD151 and α6β1 integrin, as well as ECFC α6β1 integrin and Src-PI3K signaling (Huang et al. 2016).
Expression of CD151
Comparative analysis of tetraspanin expression in various types of cancers revealed that CD151 is highly expressed in solid tumor compared with nonsolid tumor. CD151 is usually localized to the basal and lateral junctions of tumor cells. Solid tumors exhibit heterogeneity of neoplastic and normal cells at histological, genetic, and gene expression levels. Considerable heterogeneity of CD151expression was reported in various tumor tissues. The intensity of staining was noticeably weaker in well-differentiated cells of oral squamous cell carcinoma. The gradient of CD151 expression was particularly prominent in the invasive front of tumors. Overexpression of CD151 can be correlated with large tumor size, depth of invasion, and advanced stage of tumor. Optimal separation between low and high risk for overall survival and prognostic factors are usually considered as an optimized cutoff point. CD151 expression has been shown to positively correlate with stage and inversely correlate with patient survival and disease-free survival. Importantly in the use of a prognostic biomarker, CD151 expression was strongly linked to overall survival in women with stage II and III cancers and also shown to be an independent marker in this cohort. In addition, the greatest number of CD151-positive cases occurred in the HER2 subtype, which is in contrast to the more stringent prediction of CD151 occurring in HER2-negative tumors (Ke et al. 2016). Therefore, there may be additional breast cancer subtypes observed within the HER2 subtype. The cutoff point of CD151 in ER-negative breast cancer patient was reported as 14% and 31%, lung cancer patient as 50%, and gastric cancer patients as >50% using immunohistochemical and RT-PCR analysis. These studies show the cutoff values to identify CD151 positivity which may vary based on cancer type. However, large-scale prospective and retrospective studies on various cancers established CD151 as a prognostic marker for cancer therapy with minimal side effects on normal cells (Kwon et al. 2012).
Exosomes and CD151 in Cancer Metastasis
Exosomes are membrane vesicles of endocytic origin and secreted abundantly by cancer cells. They play an important role as intercellular communicators. They are defined by size, buoyant density, lipid composition, and protein markers. Tetraspanin-enriched microdomains (TEM) are endocytosis prone membrane microdomains and most widely used to characterize extracellular vesicles such as exosomes. This feature becomes of particular interest for tetraspanins that are engaged in metastasis formation such as CD151. CD151 preferentially associates with laminin (LN)-binding integrins, which supports migration via integrin trafficking and activation by Ras, Rac1, and Cdc42 recruitment; cell motility via proteases; and induction of MMP9 expression, and anchors MMP7 at the cell membrane by MMP9 binding. CD151 also associates with MMP14 and regulates ADAM10 and ADAM17 activity by recruitment into TEM. Finally, a cathepsinB or uPAR knockdown inhibits CD151-α3β1-mediated cell adhesion and invasion. Finally, a CD151 molecule with a mutation of the sorting motif in the C-terminal domain markedly attenuates endocytosis of CD151-associated α3β1, α5β1, and α6β1 which could affect CD151-supported exosome activity (Yue et al. 2015).
CD151 is an important tetraspanin in the maintenance of cellular integrity and cell communication. It also imparts the role of CD151 in cancer cell migration, invasion, and metastasis. Thus, CD151 can be proved as an important target in cancer therapy. CD151 web can be disrupted using monoclonal antibodies (mAb), shRNA, or gene knockout. Understanding the mechanism of palmitoylation of CD151 may give a wide scope for cancer research. Studying the role of CD151 in molecular mechanisms associated with self-renewal, differentiation, DNA damage response, epigenetic mechanisms, and anchorage-dependent and anchorage-independent tumor cell survival using gene silencing methods may provide an ample scope for future cancer research.
This work was supported by GITAM University, Visakhapatnam, India and funded by Department of Science and Technology (DST), New Delhi, India.
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