Cdc42 in Actin Dynamics: An Ordered Pathway Governed by Complex Equilibria and Directional Effector Handover

Overview

Journal Small GTPases

Specialties Biochemistry
Cell Biology

Date 2016 Oct 8

PMID 27715449

Citations 24

Authors

Joanna R Watson

Darerca Owen

Helen R Mott

Affiliations

Soon will be listed here.

Abstract

The small GTPase, Cdc42, is a key regulator of actin dynamics, functioning to connect multiple signals to actin polymerization through effector proteins of the Wiskott-Aldrich syndrome protein (WASP) and Transducer of Cdc42-dependent actin assembly (TOCA) families. WASP family members serve to couple Cdc42 with the actin nucleator, the Arp2/3 complex, via direct interactions. The regulation of these proteins in the context of actin dynamics has been extensively studied. Studies on the TOCA family, however, are more limited and relatively little is known about their roles and regulation. In this commentary we highlight new structural and biophysical insight into the involvement of TOCA proteins in the pathway of Cdc42-dependent actin dynamics. We discuss the biological implications of the low affinity interactions between the TOCA family and Cdc42, as well as probing the sequential binding of TOCA1 and the WASP homolog, N-WASP, to Cdc42. We place our current research in the context of the wealth of biophysical, structural and functional data from earlier studies pertaining to the Cdc42/N-WASP/Arp2/3 pathway of actin polymerization. Finally, we describe the molecular basis for a sequential G protein-effector handover from TOCA1 to N-WASP.

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References

Ridley A, Hall A . The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell. 1992; 70(3):389-99. DOI: 10.1016/0092-8674(92)90163-7. View

Hemsath L, Dvorsky R, Fiegen D, Carlier M, Ahmadian M . An electrostatic steering mechanism of Cdc42 recognition by Wiskott-Aldrich syndrome proteins. Mol Cell. 2005; 20(2):313-24. DOI: 10.1016/j.molcel.2005.08.036. View

Rohatgi R, Ho H, Kirschner M . Mechanism of N-WASP activation by CDC42 and phosphatidylinositol 4, 5-bisphosphate. J Cell Biol. 2000; 150(6):1299-310. PMC: 2150699. DOI: 10.1083/jcb.150.6.1299. View

Tsujita K, Takenawa T, Itoh T . Feedback regulation between plasma membrane tension and membrane-bending proteins organizes cell polarity during leading edge formation. Nat Cell Biol. 2015; 17(6):749-58. DOI: 10.1038/ncb3162. View

Ramesh N, Anton I, Hartwig J, Geha R . WIP, a protein associated with wiskott-aldrich syndrome protein, induces actin polymerization and redistribution in lymphoid cells. Proc Natl Acad Sci U S A. 1998; 94(26):14671-6. PMC: 25088. DOI: 10.1073/pnas.94.26.14671. View

Chander H, Truesdell P, Meens J, Craig A . Transducer of Cdc42-dependent actin assembly promotes breast cancer invasion and metastasis. Oncogene. 2012; 32(25):3080-90. DOI: 10.1038/onc.2012.317. View

Lee K, Gallop J, Rambani K, Kirschner M . Self-assembly of filopodia-like structures on supported lipid bilayers. Science. 2010; 329(5997):1341-5. PMC: 2982780. DOI: 10.1126/science.1191710. View

Mott H, Owen D . Structures of Ras superfamily effector complexes: What have we learnt in two decades?. Crit Rev Biochem Mol Biol. 2015; 50(2):85-133. DOI: 10.3109/10409238.2014.999191. View

Etienne-Manneville S . Cdc42--the centre of polarity. J Cell Sci. 2004; 117(Pt 8):1291-300. DOI: 10.1242/jcs.01115. View

10.

Kaksonen M, Toret C, Drubin D . Harnessing actin dynamics for clathrin-mediated endocytosis. Nat Rev Mol Cell Biol. 2006; 7(6):404-14. DOI: 10.1038/nrm1940. View

11.

Drubin D, Nelson W . Origins of cell polarity. Cell. 1996; 84(3):335-44. DOI: 10.1016/s0092-8674(00)81278-7. View

12.

Papayannopoulos V, Co C, Prehoda K, Snapper S, Taunton J, Lim W . A polybasic motif allows N-WASP to act as a sensor of PIP(2) density. Mol Cell. 2005; 17(2):181-91. DOI: 10.1016/j.molcel.2004.11.054. View

13.

Prehoda K, Scott J, Mullins R, Lim W . Integration of multiple signals through cooperative regulation of the N-WASP-Arp2/3 complex. Science. 2000; 290(5492):801-6. DOI: 10.1126/science.290.5492.801. View

14.

Tsujita K, Suetsugu S, Sasaki N, Furutani M, Oikawa T, Takenawa T . Coordination between the actin cytoskeleton and membrane deformation by a novel membrane tubulation domain of PCH proteins is involved in endocytosis. J Cell Biol. 2006; 172(2):269-79. PMC: 2063556. DOI: 10.1083/jcb.200508091. View

15.

Watson J, Fox H, Nietlispach D, Gallop J, Owen D, Mott H . Investigation of the Interaction between Cdc42 and Its Effector TOCA1: HANDOVER OF Cdc42 TO THE ACTIN REGULATOR N-WASP IS FACILITATED BY DIFFERENTIAL BINDING AFFINITIES. J Biol Chem. 2016; 291(26):13875-90. PMC: 4919469. DOI: 10.1074/jbc.M116.724294. View

16.

Rudolph M, Bayer P, Abo A, Kuhlmann J, Vetter I, Wittinghofer A . The Cdc42/Rac interactive binding region motif of the Wiskott Aldrich syndrome protein (WASP) is necessary but not sufficient for tight binding to Cdc42 and structure formation. J Biol Chem. 1998; 273(29):18067-76. DOI: 10.1074/jbc.273.29.18067. View

17.

Ma L, Rohatgi R, Kirschner M . The Arp2/3 complex mediates actin polymerization induced by the small GTP-binding protein Cdc42. Proc Natl Acad Sci U S A. 1998; 95(26):15362-7. PMC: 28048. DOI: 10.1073/pnas.95.26.15362. View

18.

Field C, Li R, Oegema K . Cytokinesis in eukaryotes: a mechanistic comparison. Curr Opin Cell Biol. 1999; 11(1):68-80. DOI: 10.1016/s0955-0674(99)80009-x. View

19.

Symons M, Derry J, Karlak B, Jiang S, Lemahieu V, McCormick F . Wiskott-Aldrich syndrome protein, a novel effector for the GTPase CDC42Hs, is implicated in actin polymerization. Cell. 1996; 84(5):723-34. DOI: 10.1016/s0092-8674(00)81050-8. View

20.

Kakimoto T, Katoh H, Negishi M . Regulation of neuronal morphology by Toca-1, an F-BAR/EFC protein that induces plasma membrane invagination. J Biol Chem. 2006; 281(39):29042-53. DOI: 10.1074/jbc.M604025200. View