Elsevier

Developmental Biology

Volume 341, Issue 2, 15 May 2010, Pages 464-471
Developmental Biology

The CRAL/TRIO and GOLD domain protein TAP-1 regulates RAF-1 activation

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Abstract

The activation of the protein kinase Raf at the cell membrane is a critical step in cell signaling during development, but the mechanisms that regulate Raf activity remain incompletely defined. We previously demonstrated that the C. elegans cgr-1 gene encodes a CRAL/TRIO domain-containing protein that is a critical modulator of Ras-dependent cell fate specification during C. elegans development. Here we identify the mammalian α-tocopherol associated protein-1 (TAP-1) as a functional ortholog of cgr-1. TAP-1 mRNA was expressed in many tissues, and TAP-1 protein colocalized with Ras and Raf at the cell membrane. Reducing TAP-1 expression by RNA interference increased Ras/ERK signaling in multiple cell types. These functional studies demonstrate that CRAL/TRIO domain proteins play a conserved role in regulating Ras signaling. Biochemical analyses indicated that TAP-1 operates at the level of Raf, since TAP-1 function negatively regulated the amount of Raf-1 recruited to GTP-bound Ras at the cell membrane. TAP-1 plays a significant physiological role in controlling cell division, since reducing TAP-1 expression increased the oncogenic capacity of Ras transformed human cancer cell lines. These studies identify TAP-1 as a critical modulator of Ras-mediated cellular signaling.

Abbreviations

RBD
Ras binding domain
GOLD
Golgi dynamics
CRAL/TRIO
cellular retinaldehyde and TRIO domain
TAP
tocopherol associated protein
CGR-1
CRAL/TRIO and GOLD domain suppressor of activated Ras

Keywords

Ras signaling pathway
Raf
CRAL/TRIO
GOLD
TAP-1
CGR-1
Cancer

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