LRIG1 Is a Novel Negative Regulator of the Met Receptor and Opposes Met and Her2 Synergy

Abstract

The Met receptor tyrosine kinase regulates a complex array of cellular behaviors collectively known as “invasive growth.” While essential for normal development and wound repair, this program is frequently co-opted by tumors to promote their own growth, motility, and invasion. Met is overexpressed in a variety of human tumors, and this aberrant expression correlates with poor patient prognosis. Previous studies indicate that Met receptor levels are governed in part by cbl-mediated ubiquitination and degradation, and uncoupling of Met from cbl-mediated ubiquitination promotes its transforming activity. Here we describe a novel mechanism for Met degradation. We find that the Met receptor interacts with the transmembrane protein LRIG1 independent of hepatocyte growth factor (HGF) stimulation and that LRIG1 destabilizes the Met receptor in a cbl-independent manner. Overexpression of LRIG1 destabilizes endogenous Met receptor in breast cancer cells and impairs their ability to respond to HGF. LRIG1 knockdown increases Met receptor half-life, indicating that it plays an essential role in Met degradation. Finally, LRIG1 opposes Met synergy with the ErbB2/Her2 receptor tyrosine kinase in driving cellular invasion. We conclude that LRIG1 is a novel suppressor of Met function, serving to regulate cellular receptor levels by promoting Met degradation in a ligand- and cbl-independent manner.

This work was supported by NIH grants CA118384 (C.S.) and GM068994 (K.C.) and a UC Davis Health System Award (C.S.). D.S. and J.M. are each recipients of Department of Defense Breast Cancer Research Program predoctoral fellowships.

We thank Andrew G. Manford for assistance in cloning the Met receptor cDNA, Haken Hedman for the gift of LRIG1-151 antibody, Paola Marignani for the gift of the pMX-pie and pJ6Ωpuro vectors and HEK293GPG cells, Hamid Band for the HA-c-Cbl and HA-70Z-Cbl constructs, Andrea Morrione for the HA-tagged ubiquitin construct, Yun Qiu for the pLentiLox 3.7 vector, and Ted M. Dawson for the pRK5-UB-KO construct.