Abstract
The ARHGAP35 gene encoding p190A RhoGAP (p190A) is significantly altered by both mutation and allelic deletion in human cancer, but the functional implications of such alterations are not known. Here, we demonstrate for the first time that p190A is a tumor suppressor using a xenograft mouse model with carcinoma cells harboring defined ARHGAP35 alterations. In vitro, restoration of p190A expression in carcinoma cells promotes contact inhibition of proliferation (CIP) through activation of LATS kinases and phosphorylation of the proto-oncogenic transcriptional co-activator YAP. In contrast, p190A forms harboring recurrent cancer mutations exhibit loss of function in modulating the Hippo pathway, inducing CIP, as well as attenuated suppression of tumor growth in mice. We determine that p190A promotes mesenchymal to epithelial transition (MET) and elicits expression of a cassette of epithelial adherens junction-associated genes in a cell density-dependent manner. This cassette includes CDH1 encoding E-cadherin, which amplifies p190A-mediated LATS activation and is necessary for CIP. Oppositely, we establish that p190A is obligatory for E-cadherin to activate LATS kinases and induce CIP. Collectively, this work defines a novel mechanism by which p190A and E-cadherin cooperate in modulating Hippo signaling to suppress tumor cell growth.
Highlights
Over the past decade large-scale pan-cancer genome sequencing efforts have provided a detailed mutational landscape of human cancer and identified a group of 30–40 of highly significantly mutated genes [1, 2]
We demonstrate that p190A activates LATS kinases and promotes contact inhibition of proliferation (CIP) through induced expression of E-cadherin at high cell density
ARHGAP35 mutations are found in ~4% of NSCLC, mainly tumors characterized by the absence of oncogenic driver mutations in the receptor tyrosine kinases (RTKs)–RAS–ERK pathway [4]
Summary
Over the past decade large-scale pan-cancer genome sequencing efforts have provided a detailed mutational landscape of human cancer and identified a group of 30–40 of highly significantly mutated genes [1, 2]. With the exception of ARHGAP35, all genes in this group were already strongly linked to cancer. The mutational spectrum for ARHGAP35 is suggestive of a tumor suppressor function [1, 2]. The ARHGAP35 gene is located at Chr. 19q13.32, a region that is frequently deleted in human cancer [3].
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