Interaction of p190A RhoGAP with eIF3A and Other Translation Preinitiation Factors Suggests a Role in Protein Biosynthesis

Abstract

The negative regulator of Rho family GTPases, p190A RhoGAP, is one of six mammalian proteins harboring so-called FF motifs. To explore the function of these and other p190A segments, we identified interacting proteins by tandem mass spectrometry. Here we report that endogenous human p190A, but not its 50% identical p190B paralog, associates with all 13 eIF3 subunits and several other translational preinitiation factors. The interaction involves the first FF motif of p190A and the winged helix/PCI domain of eIF3A, is enhanced by serum stimulation and reduced by phosphatase treatment. The p190A/eIF3A interaction is unaffected by mutating phosphorylated p190A-Tyr, but disrupted by a S296A mutation, targeting the only other known phosphorylated residue in the first FF domain. The p190A-eIF3 complex is distinct from eIF3 complexes containing S6K1 or mammalian target of rapamycin (mTOR), and appears to represent an incomplete preinitiation complex lacking several subunits. Based on these findings we propose that p190A may affect protein translation by controlling the assembly of functional preinitiation complexes. Whether such a role helps to explain why, unique among the large family of RhoGAPs, p190A exhibits a significantly increased mutation rate in cancer remains to be determined.

p190RhoGAPs, the ARHGAP35- and ARHGAP5-Encoded Proteins, in Health and Disease

“…These FF domains are usually found in nuclear RNA-regulating proteins, making p190RhoGAPs the only cytoplasmic proteins containing FF domains. This region has been implicated in interactions with proteins like the transcription factor TFII-I [15] or the translation preinitiation factor eiF3A [16] (Figure 2). These interactions have been reported to be regulated by phosphorylation.…”

p190A RhoGAP induces CDH1 expression and cooperates with E-cadherin to activate LATS kinases and suppress tumor cell growth

“…ARHGAP35 encodes p190A RhoGAP (p190A), a large GTPase activating protein with functions implicated in cell adhesion, cell migration, cytokinesis, ciliogenesis, entosis, gene transcription, and protein translation [5][6][7][8][9][10][11][12]. Accordingly, ARHGAP35 is an essential gene, and p190A indeed exerts pivotal functions in development [13,14].…”

“…At the molecular level, the most well-established function of p190A is to promote GTP hydrolysis on Rho GTPases [15]. In addition, motifs in p190A confer scaffolding activities through interactions with p120 RasGAP, TFII-I transcription factors, Rnd proteins, p120-catenin, EIF3 elongation initiation factors, and others [6,11,12,[16][17][18][19][20]. Prevailing evidence suggest that both catalytic and scaffolding functions are subject to posttranslational control with protein kinases playing important roles [16,[21][22][23][24][25][26].…”

p190A inactivating mutations cause aberrant RhoA activation and promote malignant transformation via the Hippo-YAP pathway in endometrial cancer

“…Scale bar, 100 μm p190A mutations promote malignant transformation of endometrial cancer cells through pathways other than the RhoA-YAP axis, given that RhoA-independent functions of p190A have been reported. 25,26 It will also be useful to generate mouse models of conditional endometrial-specific p190A KO to further investigate p190A-null phenotypes in vivo and determine whether the Hippo-YAP pathway is indispensable for p190A mutation-induced endometrial cancer.…”