A direct role for Met endocytosis in tumorigenesis

Abstract

Compartmentalization of signals generated by receptor tyrosine kinase (RTK) endocytosis has emerged as a major determinant of various cell functions. Here, using tumour-associated Met-activating mutations, we demonstrate a direct link between endocytosis and tumorigenicity. Met mutants exhibit increased endocytosis/recycling activity and decreased levels of degradation, leading to accumulation on endosomes, activation of the GTPase Rac1, loss of actin stress fibres and increased levels of cell migration. Blocking endocytosis inhibited mutants' anchorage-independent growth, in vivo tumorigenesis and metastasis while maintaining their activation. One mutant resistant to inhibition by a Met-specific tyrosine kinase inhibitor was sensitive to endocytosis inhibition. Thus, oncogenicity of Met mutants results not only from activation but also from their altered endocytic trafficking, indicating that endosomal signalling may be a crucial mechanism regulating RTK-dependent tumorigenesis.

Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis

“…Endocytosis is one of the cellular functions dampened during hypoxia (3,4,12). Endocytosis is a complex energy-consuming cellular process.…”

Spatio‐Temporal Parameters of Endosomal Signaling in Cancer: Implications for New Treatment Options

“…Therefore, combination of conventional anti‐cancer treatment with more specific interference with Met targeting to late endosomes, formation of specific signaling complexes on late endosomes or their activation from late endosomes might possibly be an alternative strategy in the future cancer therapies in addition to specific anti Met drugs being tested now on patients in clinical trials. This possibility was originally demonstrated on HGF/Met signaling dependent tumor progression, stimulated by two distinct activating mutations in the kinase domain of Met [Joffre et al, 2011] and shown recently also in a hepatocellular carcinoma (HCC) model [Hu et al, 2015]. HGF‐induced intrahepatic metastasis in mice, injected with the human hepatoma cell line HepG2, were prevented by Dynasore, the inhibitor of dynamin and endocytosis, suggesting novel therapeutic endosomal targets for the treatment of HGF‐induced HCC.…”

“…In vivo tumorigenicity of oncogenic Met mutants was demonstrated to be caused by their accumulation and signaling on endosomes, therefore, directly linking RTK endocytosis and cancer development. Constitutively active Met, mutated in the kinase domain (M1268T or D1246N), exhibits increased recycling and decreased degradation, leading to accumulation on endosomes and, therefore, sustained activation of the Rac1, enhanced cell migration and metastasis [Joffre et al, 2011]. …”

EGF inhibits constitutive internalization and palmitoylation-dependent degradation of membrane-spanning procancer CDCP1 promoting its availability on the cell surface

“…To further examine the effect of palmitoylation on CDCP1, we followed internalization of wildtype and palmitoylation deficient CDCP1 under basal conditions using a biotinylation internalization assay (30). In this assay internalization of cell surface biotinylated proteins is followed for 0.5, 1, 2 and 8 h. Chemical removal of residual cell surface biotin tagged proteins before cell lysis using 2-mercaptoethanesulfonic acid sodium salt (MeSNA) ensures Western blot analysis detects only protein trafficked to the cytoplasm ( Figure 3C, upper).…”