Linking Endocytosis and Tumorigenicity

Science Signaling  12 Jul 2011:
Vol. 4, Issue 181, pp. ec190
DOI: 10.1126/scisignal.4181ec190

Aberrant activation of growth factor receptor tyrosine kinases (RTKs) is linked to many types of cancers. Additionally, alterations in RTK internalization, trafficking, and compartmentalized signaling (for example, at endosomes) have been implicated in cancer progression. Using constitutively active mutants of the RTK Met identified originally in human carcinomas (MetD1246N and MetM1268T), Joffre et al. showed that activation alone was not sufficient for oncogenicity, but rather persistent signaling from endosomes was also required. In NIH3T3 cells stably transfected with murine MetD1246N or MetM1268T, mutant receptors exhibited greater colocalization with early and recycling endosomal markers compared with cells transfected with wild-type Met. Assays with biotin labeling revealed increased internalization and recycling of the Met mutants, but impaired degradation, thus accounting for the accumulation of Met mutants on endosomes. Inhibition of constitutive endocytosis of the Met mutants decreased the Met-induced activation of the guanosine triphosphatase Rac1, restored actin stress fibers, and reduced cell migration and anchorage-independent growth. In a mouse xenograft cancer model, tumors generated from cells expressing the MetM1268T mutant and also treated with a chemical inhibitor of endocytosis (“dynasore”) or clathrin heavy chain (CHC) short hairpin RNA (shRNA) showed a reduced volume, compared with tumors from MetM1268T controls that were treated with dimethylsulfoxide or control shRNA. However, the dynasore or CHC shRNA treatments did not decrease the phosphorylation of the Met mutants, and thus activation state, in the tumors. Thus, the authors concluded that the tumorigenicity associated with constitutively active MetD1246N and MetM1268T is linked to their enhanced accumulation and signaling from endosomes. As such, interfering with endosome-specific RTK signaling and protein interactions may be a selective way to inhibit these oncogenic receptor mutants.

C. Joffre, R. Barrow, L. Ménard, V. Calleja, I. R. Hart, S. Kermorgant, A direct role for Met endocytosis in tumorigenesis. Nat. Cell Biol. 13, 827–837 (2011). [PubMed]