The insulin resistance Grb14 adaptor protein promotes thyroid cancer ret signaling and progression

The growth factor receptor-bound protein (Grb) 14 is an adaptor molecule of the Grb7/10/14 family with characteristic Between Plekstrin and SH2 (BPS) domains serving to avidly bind tyrosine kinases. Grb14 inhibits insulin receptor (IR) catalytic activity through interaction with the BPS domain and impedes peptide substrate binding. Members of this Grb family have also been shown to interact with other kinases through their SH2 domain. Here we examined the functional role of Grb14 in thyroid cancer using loss- and gain-of-function approaches. Stable knockdown of Grb14 in thyroid cancer cells facilitated IR signaling. In contrast, RET phosphorylation was diminished in concert with reduced activation of Akt and signal transducer and activator of transcription 3 (STAT3). Loss of Grb14 also resulted in diminished cell proliferation and invasion both in vitro and in mouse flank xenografts. In complementary studies, forced expression of Grb14 interrupted IR signaling but facilitated RET activation, STAT3 and Akt phosphorylation. Consistent with these findings Grb14 overexpression enhanced cell invasion and resulted in striking metastases in an orthotopic thyroid cancer mouse xenograft model. Primary human thyroid cancer microarrays revealed a positive correlation between Grb14 expression and invasive behavior. Our findings uncover a new role for Grb14 in finely tuning receptor signaling and modulating thyroid cancer progression.