Ral signals through a MAP4 Kinase-p38 MAP kinase cascade in C. elegans cell fate patterning.

Abstract

C. elegans vulval precursor cell (VPC) fates are patterned by an EGF gradient. High dose EGF induces 1{degrees} VPC fate, while lower dose EGF contributes to 2{degrees} fate in support of LIN-12/Notch. We previously showed that the EGF 2{degrees}-promoting signal is mediated by LET-60/Ras switching effectors, from the canonical Raf-MEK-ERK MAP kinase cascade that promotes 1{degrees} fate to the non-canonical RalGEF-Ral that promotes 2{degrees} fate. Of oncogenic Ras effectors, RalGEF-Ral is by far the least well-understood. We use genetic analysis to identify an effector cascade downstream of C. elegans RAL-1/Ral, starting with an established Ral binding partner, Exo84 of the exocyst complex. Additionally, RAL-1 signals through GCK-2, a CNH domain-containing MAP4 kinase, and PMK-1/p38 MAP kinase cascade to promote 2{degrees} fate. Our study delineates a Ral-dependent developmental signaling cascade in vivo, thus providing the mechanism by which lower EGF dose is transduced.