title: Structural mechanisms of plexin signaling.
abstract: Signaling through plexin, the major cell surface receptor for semaphorin, plays critical roles in regulating processes such as neuronal axon guidance, angiogenesis and immune response. Plexin is normally kept inactive in the absence of semaphorin. Upon binding of semaphorin to the extracellular region, plexin is activated and transduces signal to the inside of the cell through its cytoplasmic region. The GTPase Activating Protein (GAP) domain in the plexin cytoplasmic region mediates the major intracellular signaling pathway. The substrate specificity and regulation mechanisms of the GAP domain have only been revealed recently. Many intracellular proteins serve as either upstream regulators or downstream transducers by directly interacting with plexin. The mechanisms of action for some of these proteins also start to emerge from recent studies. We review here these advances in the mechanistic understanding of plexin intracellular signaling from a structural perspective.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Heath G
authors.initials: HG
authors.lastname: Pascoe
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Yuxiao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: Xuewu.zhang@utsouthwestern.edu.
authors.forename: Xuewu
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D009419:Nerve Tissue Proteins; C091529:plexin; D020741:rho GTP-Binding Proteins
keywords: Dimerization; GAP; Plexin; Rap; Signaling
references.citation: Protein Sci. 2009 May;18(5):1060-71
references.pmid: 19388051
references.citation: EMBO Rep. 2009 Jun;10(6):614-21
references.pmid: 19444311
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15610-5
references.pmid: 19717441
references.citation: J Biol Chem. 2009 Dec 18;284(51):35962-72
references.pmid: 19843518
references.citation: EMBO J. 2010 Apr 7;29(7):1205-14
references.pmid: 20186121
references.citation: Mol Cell Biol. 2010 Jun;30(12):3086-98
references.pmid: 20385769
references.citation: Neuron. 2002 Jul 3;35(1):51-63
references.pmid: 12123608
references.citation: Biochem Biophys Res Commun. 2002 Sep 13;297(1):32-7
references.pmid: 12220504
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12085-90
references.pmid: 12196628
references.citation: FEBS Lett. 2002 Oct 9;529(2-3):168-72
references.pmid: 12372594
references.citation: J Biol Chem. 2002 Nov 8;277(45):43115-20
references.pmid: 12183458
references.citation: J Biol Chem. 2003 Jul 11;278(28):25671-7
references.pmid: 12730235
references.citation: Neuron. 2003 Aug 14;39(4):589-98
references.pmid: 12925274
references.citation: Nat Struct Biol. 2003 Oct;10(10):843-8
references.pmid: 12958590
references.citation: J Biol Chem. 2004 Aug 6;279(32):33199-205
references.pmid: 15187088
references.citation: Exp Mol Med. 2010 May 31;42(5):335-44
references.pmid: 20200473
references.citation: Cell. 2010 Sep 3;142(5):749-61
references.pmid: 20727575
references.citation: Nature. 2010 Oct 28;467(7319):1118-22
references.pmid: 20877282
references.citation: Nature. 2010 Oct 28;467(7319):1123-7
references.pmid: 20881961
references.citation: Dev Biol. 2011 Jan 1;349(1):1-19
references.pmid: 20880496
references.citation: J Biol Chem. 2011 Jul 22;286(29):26093-106
references.pmid: 21610070
references.citation: J Biol Chem. 2000 Jun 30;275(26):20020-6
references.pmid: 10777492
references.citation: Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12457-62
references.pmid: 11035813
references.citation: FEBS Lett. 2000 Dec 1;486(1):68-72
references.pmid: 11108845
references.citation: Neuron. 2001 Feb;29(2):429-39
references.pmid: 11239433
references.citation: Curr Biol. 2001 Mar 6;11(5):339-44
references.pmid: 11267870
references.citation: Neuron. 2001 Oct 11;32(1):39-51
references.pmid: 11604137
references.citation: J Neurosci. 2002 Jan 15;22(2):471-7
references.pmid: 11784792
references.citation: Genes Dev. 2002 Apr 1;16(7):836-45
references.pmid: 11937491
references.citation: Science. 2004 Aug 6;305(5685):862-5
references.pmid: 15297673
references.citation: Neuron. 2004 Aug 19;43(4):563-74
references.pmid: 15312654
references.citation: J Biol Chem. 1990 May 5;265(13):7104-7
references.pmid: 2158984
references.citation: Science. 1990 Jul 13;249(4965):169-71
references.pmid: 2164710
references.citation: J Biol Chem. 1991 Nov 25;266(33):22222-6
references.pmid: 1939245
references.citation: Cell. 1993 Dec 31;75(7):1389-99
references.pmid: 8269517
references.citation: Science. 1997 Jul 18;277(5324):333-8
references.pmid: 9219684
references.citation: J Biol Chem. 1997 Aug 1;272(31):19328-32
references.pmid: 9235929
references.citation: J Neurosci. 1997 Aug 15;17(16):6256-63
references.pmid: 9236236
references.citation: J Biol Chem. 1998 Mar 27;273(13):7326-31
references.pmid: 9516427
references.citation: J Biol Chem. 1998 Jun 19;273(25):15708-13
references.pmid: 9624167
references.citation: EMBO J. 1998 Aug 3;17(15):4313-27
references.pmid: 9687500
references.citation: Neuron. 1998 Nov;21(5):1093-100
references.pmid: 9856464
references.citation: Cell. 1998 Dec 23;95(7):903-16
references.pmid: 9875845
references.citation: J Neurosci. 1999 Mar 15;19(6):1965-75
references.pmid: 10066250
references.citation: Cell. 1999 May 28;97(5):551-2
references.pmid: 10367884
references.citation: J Biol Chem. 1999 Aug 20;274(34):23850-7
references.pmid: 10446149
references.citation: Cell. 1999 Oct 1;99(1):59-69
references.pmid: 10520994
references.citation: Cell. 1999 Oct 1;99(1):71-80
references.pmid: 10520995
references.citation: J Biol Chem. 2005 Sep 23;280(38):33026-34
references.pmid: 16014623
references.citation: Nat Neurosci. 2005 Dec;8(12):1712-9
references.pmid: 16286926
references.citation: Nat Rev Mol Cell Biol. 2005 Oct;6(10):789-800
references.pmid: 16314868
references.citation: J Biol Chem. 2006 Apr 14;281(15):9891-900
references.pmid: 16431904
references.citation: Cell. 2007 Jun 1;129(5):865-77
references.pmid: 17540168
references.citation: Annu Rev Cell Dev Biol. 2007;23:263-92
references.pmid: 17539753
references.citation: PLoS Biol. 2011 Aug;9(8):e1001134
references.pmid: 21912513
references.citation: Trends Cell Biol. 2011 Oct;21(10):615-23
references.pmid: 21820312
references.citation: Cell Res. 2012 Jan;22(1):23-32
references.pmid: 22157652
references.citation: Sci Signal. 2012 Jan 17;5(207):ra6
references.pmid: 22253263
references.citation: Trends Immunol. 2012 Mar;33(3):127-35
references.pmid: 22325954
references.citation: Nature. 2012 May 3;485(7396):69-74
references.pmid: 22522930
references.citation: Mol Cell Neurosci. 2012 Jun;50(2):193-200
references.pmid: 22564823
references.citation: Cancer Cell. 2012 Aug 14;22(2):145-52
references.pmid: 22897846
references.citation: Cell Mol Life Sci. 2012 Nov;69(22):3765-805
references.pmid: 22744749
references.citation: Nat Struct Mol Biol. 2012 Dec;19(12):1293-9
references.pmid: 23104057
references.citation: Structure. 2013 Mar 5;21(3):355-64
references.pmid: 23375260
references.citation: Semin Cell Dev Biol. 2013 Mar;24(3):163-71
references.pmid: 23022498
references.citation: Semin Cell Dev Biol. 2013 Mar;24(3):139-45
references.pmid: 23253452
references.citation: Exp Cell Res. 2013 May 15;319(9):1306-16
references.pmid: 23422037
references.citation: Biochem Biophys Res Commun. 2013 May 17;434(4):785-90
references.pmid: 23603360
references.citation: Elife. 2013;2:e01279
references.pmid: 24137545
references.citation: Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):2194-9
references.pmid: 24469813
references.citation: Nat Rev Drug Discov. 2014 Aug;13(8):603-21
references.pmid: 25082288
references.citation: J Biol Chem. 2014 Oct 24;289(43):29545-57
references.pmid: 25193662
references.citation: Nat Cell Biol. 2015 Jan;17(1):81-94
references.pmid: 25531777
references.citation: Philos Trans A Math Phys Eng Sci. 2015 Mar 6;373(2036). pii: 20130155. doi: 10.1098/rsta.2013.0155
references.pmid: 25624520
references.citation: J Biol Chem. 2007 Dec 21;282(51):37215-24
references.pmid: 17916560
references.citation: EMBO Rep. 2008 Apr;9(4):350-5
references.pmid: 18323856
references.citation: EMBO J. 2008 Apr 9;27(7):1145-53
references.pmid: 18309292
references.citation: Neuron. 2009 Feb 12;61(3):359-72
references.pmid: 19217374