A RAC/CDC-42–Independent GIT/PIX/PAK Signaling Pathway Mediates Cell Migration in C. elegans

Mark Lucanic,Hwai-Jong Cheng,Stuart K Kim

doi:10.1371/journal.pgen.1000269

Mark Lucanic, Hwai-Jong Cheng + Show 1 more

Open Access

https://doi.org/10.1371/journal.pgen.1000269

Copy DOI

Journal: PLoS Genetics	Publication Date: Nov 21, 2008
Citations: 95	License type: CC BY 4.0

Affiliation: University of California, Davis

Abstract

P21 activated kinase (PAK), PAK interacting exchange factor (PIX), and G protein coupled receptor kinase interactor (GIT) compose a highly conserved signaling module controlling cell migrations, immune system signaling, and the formation of the mammalian nervous system. Traditionally, this signaling module is thought to facilitate the function of RAC and CDC-42 GTPases by allowing for the recruitment of a GTPase effector (PAK), a GTPase activator (PIX), and a scaffolding protein (GIT) as a regulated signaling unit to specific subcellular locations. Instead, we report here that this signaling module functions independently of RAC/CDC-42 GTPases in vivo to control the cell shape and migration of the distal tip cells (DTCs) during morphogenesis of the Caenorhabditis elegans gonad. In addition, this RAC/CDC-42–independent PAK pathway functions in parallel to a classical GTPase/PAK pathway to control the guidance aspect of DTC migration. Among the C. elegans PAKs, only PAK-1 functions in the GIT/PIX/PAK pathway independently of RAC/CDC42 GTPases, while both PAK-1 and MAX-2 are redundantly utilized in the GTPase/PAK pathway. Both RAC/CDC42–dependent and –independent PAK pathways function with the integrin receptors, suggesting that signaling through integrins can control the morphology, movement, and guidance of DTC through discrete pathways. Collectively, our results define a new signaling capacity for the GIT/PIX/PAK module that is likely to be conserved in vertebrates and demonstrate that PAK family members, which are redundantly utilized as GTPase effectors, can act non-redundantly in pathways independent of these GTPases.

Highlights

The G protein coupled receptor kinase interactor (GIT)/PAK interacting exchange factor (PIX)/P21 activated kinase (PAK) signaling pathway is a highly conserved signaling module which controls cytoskeletal dynamics across metazoans
We find that in C. elegans the PAKs, RACs, CDC-42, GIT and PIX are all involved in gonad morphogenesis
While investigating the roles of the C. elegans PAKs we found that the two PAKs, pak-1 and max-2 are redundantly required for proper formation of the gonad

Summary

Introduction

The GIT/PIX/PAK signaling pathway is a highly conserved signaling module which controls cytoskeletal dynamics across metazoans. The functions of this signaling complex are diverse. The GIT/PIX/PAK complex has been shown to regulate neuronal plasticity and development in the nervous system [1,2,3]. The importance of this protein complex is further highlighted by the observation that in humans a loss of either PAK3 or aPIX leads to impaired function of the nervous system from nonsyndromic mental retardation [4,5]. To further understand how this complex functions in a welldefined in vivo system, we have isolated the C. elegans orthologs of the GIT/PIX/PAK complex and studied their roles in the migrations of the gonad distal tip cells (DTCs)

Methods

Results

Conclusion