PAK-PIX Interactions Regulate Adhesion Dynamics and Membrane Protrusion to Control Neurite Outgrowth

Overview

Journal J Cell Sci

Specialty Cell Biology

Date 2013 Jan 17

PMID 23321640

Citations 33

Authors

Miguel Santiago-Medina

Kelly A Gregus

Timothy M Gomez

Affiliations

Soon will be listed here.

Abstract

The roles of P21-activated kinase (PAK) in the regulation of axon outgrowth downstream of extracellular matrix (ECM) proteins are poorly understood. Here we show that PAK1-3 and PIX are expressed in the developing spinal cord and differentially localize to point contacts and filopodial tips within motile growth cones. Using a specific interfering peptide called PAK18, we found that axon outgrowth is robustly stimulated on laminin by partial inhibition of PAK-PIX interactions and PAK function, whereas complete inhibition of PAK function stalls axon outgrowth. Furthermore, modest inhibition of PAK-PIX stimulates the assembly and turnover of growth cone point contacts, whereas strong inhibition over-stabilizes adhesions. Point mutations within PAK confirm the importance of PIX binding. Together our data suggest that regulation of PAK-PIX interactions in growth cones controls neurite outgrowth by influencing the activity of several important mediators of actin filament polymerization and retrograde flow, as well as integrin-dependent adhesion to laminin.

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References

Wiggan O, Shaw A, DeLuca J, Bamburg J . ADF/cofilin regulates actomyosin assembly through competitive inhibition of myosin II binding to F-actin. Dev Cell. 2012; 22(3):530-43. PMC: 3306597. DOI: 10.1016/j.devcel.2011.12.026. View

Obermeier A, Ahmed S, Manser E, YEN S, Hall C, Lim L . PAK promotes morphological changes by acting upstream of Rac. EMBO J. 1998; 17(15):4328-39. PMC: 1170766. DOI: 10.1093/emboj/17.15.4328. View

Petchprayoon C, Suwanborirux K, Tanaka J, Yan Y, Sakata T, Marriott G . Fluorescent kabiramides: new probes to quantify actin in vitro and in vivo. Bioconjug Chem. 2005; 16(6):1382-9. DOI: 10.1021/bc050006j. View

Raymond F . X linked mental retardation: a clinical guide. J Med Genet. 2005; 43(3):193-200. PMC: 2563255. DOI: 10.1136/jmg.2005.033043. View

Galbraith C, Yamada K, Galbraith J . Polymerizing actin fibers position integrins primed to probe for adhesion sites. Science. 2007; 315(5814):992-5. DOI: 10.1126/science.1137904. View

Carlstrom L, Hines J, Henle S, Henley J . Bidirectional remodeling of β1-integrin adhesions during chemotropic regulation of nerve growth. BMC Biol. 2011; 9:82. PMC: 3283487. DOI: 10.1186/1741-7007-9-82. View

Lowery L, Van Vactor D . The trip of the tip: understanding the growth cone machinery. Nat Rev Mol Cell Biol. 2009; 10(5):332-43. PMC: 2714171. DOI: 10.1038/nrm2679. View

Bito H, Furuyashiki T, Ishihara H, Shibasaki Y, Ohashi K, Mizuno K . A critical role for a Rho-associated kinase, p160ROCK, in determining axon outgrowth in mammalian CNS neurons. Neuron. 2000; 26(2):431-41. DOI: 10.1016/s0896-6273(00)81175-7. View

Nayal A, Webb D, Brown C, Schaefer E, Vicente-Manzanares M, Horwitz A . Paxillin phosphorylation at Ser273 localizes a GIT1-PIX-PAK complex and regulates adhesion and protrusion dynamics. J Cell Biol. 2006; 173(4):587-9. PMC: 2063867. DOI: 10.1083/jcb.200509075. View

10.

Wu C, Asokan S, Berginski M, Haynes E, Sharpless N, Griffith J . Arp2/3 is critical for lamellipodia and response to extracellular matrix cues but is dispensable for chemotaxis. Cell. 2012; 148(5):973-87. PMC: 3707508. DOI: 10.1016/j.cell.2011.12.034. View

11.

Myers J, Robles E, Ducharme-Smith A, Gomez T . Focal adhesion kinase modulates Cdc42 activity downstream of positive and negative axon guidance cues. J Cell Sci. 2012; 125(Pt 12):2918-29. PMC: 3434813. DOI: 10.1242/jcs.100107. View

12.

Dent E, Gupton S, Gertler F . The growth cone cytoskeleton in axon outgrowth and guidance. Cold Spring Harb Perspect Biol. 2010; 3(3). PMC: 3039926. DOI: 10.1101/cshperspect.a001800. View

13.

Marsick B, San Miguel-Ruiz J, Letourneau P . Activation of ezrin/radixin/moesin mediates attractive growth cone guidance through regulation of growth cone actin and adhesion receptors. J Neurosci. 2012; 32(1):282-96. PMC: 3306234. DOI: 10.1523/JNEUROSCI.4794-11.2012. View

14.

Cau J, Faure S, Vigneron S, Labbe J, Delsert C, Morin N . Regulation of Xenopus p21-activated kinase (X-PAK2) by Cdc42 and maturation-promoting factor controls Xenopus oocyte maturation. J Biol Chem. 2000; 275(4):2367-75. DOI: 10.1074/jbc.275.4.2367. View

15.

Rozen S, Skaletsky H . Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol. 1999; 132:365-86. DOI: 10.1385/1-59259-192-2:365. View

16.

Marin O, Valiente M, Ge X, Tsai L . Guiding neuronal cell migrations. Cold Spring Harb Perspect Biol. 2010; 2(2):a001834. PMC: 2828271. DOI: 10.1101/cshperspect.a001834. View

17.

Sretavan D, Reichardt L . Time-lapse video analysis of retinal ganglion cell axon pathfinding at the mammalian optic chiasm: growth cone guidance using intrinsic chiasm cues. Neuron. 1993; 10(4):761-77. DOI: 10.1016/0896-6273(93)90176-r. View

18.

Zhang H, Webb D, Asmussen H, Niu S, Horwitz A . A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC. J Neurosci. 2005; 25(13):3379-88. PMC: 6724907. DOI: 10.1523/JNEUROSCI.3553-04.2005. View

19.

Heckman C, Demuth J, Deters D, Malwade S, Cayer M, Monfries C . Relationship of p21-activated kinase (PAK) and filopodia to persistence and oncogenic transformation. J Cell Physiol. 2009; 220(3):576-85. DOI: 10.1002/jcp.21788. View

20.

Bright M, Garner A, Ridley A . PAK1 and PAK2 have different roles in HGF-induced morphological responses. Cell Signal. 2009; 21(12):1738-47. DOI: 10.1016/j.cellsig.2009.07.005. View