Skip to main content
SpringerLink
Log in

Semaphorin Receptors and Their Signaling

  • Chapter
Semaphorins

Abstract

Semaphorins, which are a large family of secreted and membrane-bound molecules, were initially identified as neuronal axon-guidance signaling molecules but are now known as important key regulators for cell adhesion and motility in a wide range of organ systems, such as angiogenesis and immune response. The semaphorin receptors, neuropilins and plexins, are expressed in a variety of cell types, including neurons, endothelial cells, and cancer cells. Plexins are primarily receptors responsible for intracellular semaphorin signalings. Plexins possess an intrinsic GAP (glyceraldehyde-3-phosphate) activity for R-Ras subfamily GTPases, and this GAP activity is one of the crucial signals of semaphorins. In addition, plexins associate with a variety of signaling molecules, such as Rho GEFs and Rho GAP, and these associated molecules determine the characters of semaphorin signals. On the other hand, their signalings are critically modulated by their associated co-receptor molecules, including tyrosine kinase receptors. Semaphorins provide attractive and repulsive responses in a variety of cells, but associated co-receptors of plexins frequently hold the key to conversion between attraction and repulsion. In this chapter, we focus attention on the molecular signaling systems of plexins.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Artigiani S, Conrotto P, Fazzari P et al (2004) Plexin-B3 is a functional receptor for semaphorin 5A. EMBO Rep 5:710–714

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Aurandt J, Vikis HG, Gutkind JS et al (2002) The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG. Proc Natl Acad Sci U S A 99:12085–12090

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ayoob J, Yu H-H, Terman JR et al (2004) The Drosophila receptor guanylyl cyclase Gyc76C is required for semaphorin-1a-plexin A-mediated axonal repulsion. J Neurosci 24:6639–6649

    Article  CAS  PubMed  Google Scholar 

  • Barberis D, Casazza A, Sordella R et al (2005) p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signaling. J Cell Sci 118:4689–4700

    Article  CAS  PubMed  Google Scholar 

  • Basile JR, Gavard J, Gutkind JS (2007) Plexin-B1 utilizes RhoA and Rho kinase to promote the integrin-dependent activation of Akt and ERK and endothelial cell motility. J Biol Chem 282:34888–34895

    Article  CAS  PubMed  Google Scholar 

  • Bellon A, Luchino J, Haigh K et al (2010) VEGFR2 (KDR/FIk1) signaling mediates axon growth in response to semaphorin 3E in the developing brain. Neuron 66:205–219

    Article  CAS  PubMed  Google Scholar 

  • Brown M, Jacobs T, Eickholt B et al (2004) a2-Chimaerin, cyclin-dependent kinase 5/p35 and its target collapsin response mediator protein-2 are essential components in semaphorin 3A-induced growth cone collapse. J Neurosci 24:8994–9004

    Article  CAS  PubMed  Google Scholar 

  • Burridge K, Wennerberg K (2004) Rho and Rac take center stage. Cell 116:167–179

    Article  CAS  PubMed  Google Scholar 

  • Chauvet S, Cohen S, Yoshida Y et al (2007) Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development. Neuron 56:807–822

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Driessens MHE, Hu H, Nobes CD et al (2001) Plexin-B semaphorin receptors interact directly with active Rac and regulate the actin cytoskeleton by activating Rho. Curr Biol 11:339–344

    Article  CAS  PubMed  Google Scholar 

  • Dudanova I, Klein R (2013) Integration of guidance cues: parallel signaling and crosstalk. Trends Neurosci 36:295–304

    Article  CAS  PubMed  Google Scholar 

  • Fukata Y, Amano M, Kaibuchi K (2001) Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. Trends Pharmacol Sci 22:32–39

    Article  CAS  PubMed  Google Scholar 

  • Fukata Y, Ito T, Kimura T et al (2002) CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nat Cell Biol 4:583–591

    CAS  PubMed  Google Scholar 

  • Goshima Y, Nakamura F, Strittmatter P et al (1995) Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33. Nature (Lond) 276:509–514

    Article  Google Scholar 

  • Gu C, Yoshida Y, Livet J et al (2005) Semaphorin 3E and Plexin-D1 control vascular pattern independently of neuropilins. Science 307:265–268

    Article  CAS  PubMed  Google Scholar 

  • Hu H, Marton TF, Goodman CS (2001) Plexin B mediates axon guidance in Drosophila by simultaneously inhibiting active Rac and enhancing RhoA signaling. Neuron 32:39–51

    Article  CAS  PubMed  Google Scholar 

  • Hung RJ, Yazdani U, Yoon J et al (2010) Mical links semaphorins to F-actin disassembly. Nature (Lond) 463:823–827

    Article  CAS  Google Scholar 

  • Hung RJ, Pak CW, Terman JR (2011) Direct redox regulation of F-actin assembly and disassembly by Mical. Science 334:1710–1713

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Inatomi R, Tsujimura T, Hitomi T et al (2000) Identification of CRAM, a novel unc-33 gene family protein that associates with CRMP3 and protein-tyrosine kinase(s) in the developing rat brain. J Biol Chem 275:27291–27302

    Google Scholar 

  • Ito Y, Oinuma I, Katoh H et al (2006) Sema4D/Plexin-B1 activates GSK-3β through R-Ras GAP activity, inducing growth cone collapse. EMBO Rep 7:704–709

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jin Z, Strittmatter SM (1997) Rac1 mediates collapsing-1-induced growth cone collapse. J Neurosci 17:6256–6263

    CAS  PubMed  Google Scholar 

  • Jurney WM, Gallo G, Letourneau PC et al (2002) Rac1-mediated endocytosis during ephrin-A2- and semaphorin 3A-induced growth cone collapse. J Neurosci 22:6019–6028

    CAS  PubMed  Google Scholar 

  • Kerjan G, Dolan J, Haunaitre C et al (2005) The transmembrane semaphorin Sema6A controls cerebellar granule cell migration. Nat Neurosci 8:1516–1524

    Article  CAS  PubMed  Google Scholar 

  • Kinbara K, Goldfinger LE, Hansen M et al (2003) Ras GTPases: integrins friends or foes? Nat Rev Mol Cell Biol 4:767–776

    Article  CAS  PubMed  Google Scholar 

  • Kuwajima T, Yoshida Y, Takegahara N et al (2012) Optic chiasm presentation of semaphorin6D in the context of Plexin-A1 and Nr-CAM promotes retinal axon midline crossing. Neuron 74:676–690

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lee BC, Peterfi Z, Hoffmann FW et al (2013) MsrB1 and MICALs regulates actin assembly and macrophage function via reversible stereoselective methionine oxidation. Mol Cell 51:397–404

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Legg JA, Machesky LM (2004) MRL proteins: leading Ena/VASP to Ras GTPases. Nat Cell Biol 6:1015–1017

    Article  CAS  PubMed  Google Scholar 

  • Mitsui N, Inatomi R, Takahashi S et al (2002) Involvement of Fes/Fps tyrosine kinase in semaphorin 3A signaling. EMBO J 21:3274–3285

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Negishi M, Oinuma I, Katoh H (2005) Plexin: axon guidance and signal transduction. Cell Mol Life Sci 62:1363–1371

    Article  CAS  PubMed  Google Scholar 

  • Neufeld G, Kessler O (2008) The semaphorins: versatile regulators of tumour progression and tumour angiogenesis. Nat Rev Cancer 8:632–643

    Article  CAS  PubMed  Google Scholar 

  • Oinuma I, Ishikawa Y, Katoh H et al (2004a) The semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. Science 305:862–865

    Article  CAS  PubMed  Google Scholar 

  • Oinuma I, Katoh H, Negishi M (2004b) Molecular dissection of the semaphorin 4D receptor Plexin-B1-stimulated R-Ras GTPase-activating protein activity and neurite remodeling in hippocampal neurons. J Neurosci 24:11473–11480

    Article  CAS  PubMed  Google Scholar 

  • Oinuma I, Katoh H, Negishi M (2006) Semaphorin 4D/Plexin-B1-mediated R-Ras GAP activity inhibits cell migration by regulating β1 integrin activity. J Cell Biol 173:601–613

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Oinuma I, Ito Y, Katoh H et al (2010) Semaphorin 4D/Plexin-B1 stimulates PTEN activity through R-Ras GTPase-activating protein activity, inducing growth cone collapse in hippocampal neurons. J Biol Chem 285:28200–28209

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pasterkamp RJ, Peschon JJ, Spriggs MK et al (2003) Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature (Lond) 424:398–405

    Article  Google Scholar 

  • Perrot V, Prado J, Gutkind JS (2002) Plexin-B regulates Rho through the guanine nucleotide exchange factors leukemia-associated Rho GEF (LARG) and PDZ-RhoGEF. J Biol Chem 277:43115–43120

    Article  CAS  PubMed  Google Scholar 

  • Saito Y, Oinuma I, Fujimoto S et al (2009) Plexin-B1 is a GTPase activating protein for M-Ras, remodeling dendrite morphology. EMBO Rep 10:614–621

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sakurai A, Gavard J, Linhares Y et al (2010) Semaphorin 3E initiates antiangiogenic signaling through Plexin D1 by regulating Arf6 and R-Ras. Mol Cell Biol 30:3086–3098

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sakurai A, Jian X, Lee CJ et al (2011) Phosphatidylinositol-4-phosphate 5-kinase and GEP100/Brag2 protein mediate antiangiogenic signaling by semaphorin 3E-Plexin-D1 through Arf6 protein. J Biol Chem 286:34335–34345

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sasaki Y, Cheng C, Uchida Y et al (2002) Fyn and Cdk5 mediate semaphorin-3A signaling, which is involved in regulation of dendrite orientation in cerebral cortex. Neuron 35:907–920

    Article  CAS  PubMed  Google Scholar 

  • Scott GA, McClelland LA, Fricke AF et al (2009) Plexin C1, a receptor for semaphorin 7A, inactivates cofilin and is a potential tumor suppressor for melanoma progression. J Invest Dermatol 129:954–963

    Article  CAS  PubMed  Google Scholar 

  • Sun T, Krishnan R, Swiercz JM (2012) Grb2 mediates semaphorin-4D-dependent RhoA inactivation. J Cell Sci 125:3557–3567

    Article  CAS  PubMed  Google Scholar 

  • Suto F, Tsuboi M, Kamiya H et al (2007) Interactions between Plexin-A2, Plexin-A4, and semaphorin 6A control lamina-restricted projection of hippocampal mossy fibers. Neuron 53:535–547

    Article  CAS  PubMed  Google Scholar 

  • Suzuki K, Okuno T, Yamamoto M et al (2007) Semaphorin 7A initiates T-cell-mediated inflammatory responses through α1β1integrin. Nature (Lond) 446:680–684

    Article  CAS  Google Scholar 

  • Swiercz JM, Kuner R, Behrens J et al (2002) Plexin-B1 directly interacts with PDZ-RhoGEF/LARG to regulate RhoA and growth cone morphology. Neuron 35:51–63

    Article  CAS  PubMed  Google Scholar 

  • Swiercz JM, Kuner R, Offermanns S (2004) Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. J Cell Biol 165:869–880

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Swiercz JM, Worzfeld T, Offermanns S (2008) ErbB-2 and Met reciprocally regulate cellular signaling via Plexin-B1. J Biol Chem 283:1893–1901

    Article  CAS  PubMed  Google Scholar 

  • Swiercz JM, Worzfeld T, Offermanns S (2009) Semaphorin 4D signaling requires the recruitment of phospholipase Cγ into the plexin-B1 receptor complex. Mol Cell Biol 29:6321–6334

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Takegahara N, Takamatsu H, Toyofuku T et al (2006) Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis. Nat Cell Biol 8:615–622

    Article  CAS  PubMed  Google Scholar 

  • Tamagnone L, Artigiani S, Chen H et al (1999) Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 99:71–80

    Article  CAS  PubMed  Google Scholar 

  • Tasaka G, Negishi M, Oinuma I (2012) Semaphorin 4D/Plexin-B1-mediated M-Ras GAP activity regulates actin-based dendrite remodeling through lamellipodin. J Neurosci 32:8293–8305

    Article  CAS  PubMed  Google Scholar 

  • Terman JR, Kolodkin AL (2004) Nervy links protein kinase A to plexin-mediated semaphorin repulsion. Science 303:1204–1207

    Article  CAS  PubMed  Google Scholar 

  • Terman JR, Mao T, Pasterkamp RJ (2002) MICALs, a family of conserved flavoprotein oxidoreductases, function in plexin-mediated axonal repulsion. Cell 209:887–900

    Article  Google Scholar 

  • Togashi H, Schmidt E, Strettmatter SM (2006) RanBPM contributes to semaphorin3A signaling through Plexin-A receptors. J Neurosci 26:4961–4969

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Topper L, Mlechkovich G, Savariego D et al (2010) Cis interaction between semaphorin 6A and Plexin-A4 modulates the repulsive response to Sema6A. EMBO J 29:2635–2645

    Article  Google Scholar 

  • Toyofuku T, Zhang H, Kumanogoh A et al (2004) Guidance of myocardial patterning in cardiac development by Sema6D reverse signaling. Nat Cell Biol 6:1204–1211

    Article  CAS  PubMed  Google Scholar 

  • Toyofuku T, Yoshida J, Sugimoto T et al (2005) FARP2 triggers signals for Sema3A-mediated axonal repulsion. Nat Neurosci 8:1712–1719

    Article  CAS  PubMed  Google Scholar 

  • Uesugi K, Oinuma I, Katoh H et al (2009) Different requirement for Rnd GTPases of R-Ras GAP activity of Plexin-C1 and Plexin-D1. J Biol Chem 284:6743–6751

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Vikis HG, Li W, Guan K (2002) The plexin-B1/Rac interaction inhibits PAK activation and enhances Sema4D ligand binding. Gene Dev 16:836–845

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Walzer T, Galibert L, Comeau MR et al (2005) Plexin C1 engagement on mouse dendritic cells by viral semaphorin A39R induces actin cytoskeleton rearrangement and inhibits integrin-mediated adhesion and chemokine-induced migration. J Immunol 174:51–59

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, He H, Srivastava S et al (2012) Plexins are GTPase-activating proteins for Rap and are activated by induced dimerization. Sci Signal 5:1–12

    CAS  Google Scholar 

  • Winberg M, Tamagnone L, Bai J (2001) The transmembrane protein off-track associates with plexins and functions downstream of semaphorin signaling during axon guidance. Neuron 32:53–62

    Article  CAS  PubMed  Google Scholar 

  • Wu KY, Hengst U, Cox LJ et al (2005) Local translation of RhoA regulates growth cone collapse. Nature (Lond) 436:1020–1024

    Article  CAS  Google Scholar 

  • Zhou Y, Gunput RF, Pasterkamp RJ (2008) Semaphorin signaling: progress made and promises ahead. Trends Biochem Sci 33:161–170

    Article  CAS  PubMed  Google Scholar 

  • Zhu L et al (2007) Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury. Proc Natl Acad Sci U S A 104:1621–1626

    Article  PubMed Central  PubMed  Google Scholar 

  • Zhuang B, Su YS, Sockanathan S (2009) FARP1 promotes the dendritic growth of spinal motor neuron subtypes through transmembrane semaphorin6A and PlexinA4 signaling. Neuron 61:359–372

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zvi A, Gigi L, Klein H et al (2007) Modulation of semaphorin 3A activity by p75 neurotrophin receptor influences peripheral axon patterning. J Neurosci 27:13000–13011

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan

    Manabu Negishi & Izumi Oinuma

Authors
  1. Manabu Negishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Izumi Oinuma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Manabu Negishi .

Editor information

Editors and Affiliations

  1. Department of Respiratory Medicine Allergy and Rheumatic Diseases, Graduate School of Medicine Osaka University, Suita, Osaka, Japan

    Atsushi Kumanogoh

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Japan

About this chapter

Cite this chapter

Negishi, M., Oinuma, I. (2015). Semaphorin Receptors and Their Signaling. In: Kumanogoh, A. (eds) Semaphorins. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54385-5_1

Download citation

Publish with us

Policies and ethics

Search

Navigation