Enhanced transformation by a plasma membrane-associated met oncoprotein: activation of a phosphoinositide 3'-kinase-dependent autocrine loop involving hyaluronic acid and CD44.
A Met-hepatocyte growth factor receptor oncoprotein, Tpr-Met, generated by chromosomal rearrangement, fuses a protein dimerization motif with the cytoplasmic domain of the Met receptor, producing a cytosolic, constitutively activated tyrosine kinase. Although both the Met receptor and the Tpr-Met oncoprotein associate with the same substrates, activating mutations of the Met receptor in hereditary papillary renal carcinomas have different signaling requirements for transformation than Tpr-Met. This suggests differential activation of membrane-localized pathways by oncogenic forms of the membrane-bound Met receptor but not by the cytoplasmic Tpr-Met oncoprotein. To establish which pathways might be differentially regulated, we have localized the constitutively activated Tpr-Met oncoprotein to the membrane using the c-src myristoylation signal. Membrane localization enhances cellular transformation, focus formation, and anchorage-independent growth and induces tumors with a distinct myxoid phenotype. This correlates with the induction of hyaluronic acid (HA) and the presence of a distinct form of its receptor, CD44. A pharmacological inhibitor of phosphoinositide 3' kinase (PI3'K), inhibits the production of HA, and conversely, an activated, plasma membrane-targeted form of PI3'K is sufficient to enhance HA production. Furthermore, the multisubstrate adapter protein Gab-1, which couples the Met receptor with PI3'K, enhances Met receptor-dependent HA synthesis in a PI3'K-dependent manner. These results provide a positive link to a role for HA and CD44 in Met receptor-mediated oncogenesis and implicate PI3'K in these events.
Kamikura
D M
DM
Molecular Oncology Group, Departments of Medicine, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada H3A-1A1.
Khoury
H
H
Maroun
C
C
Naujokas
M A
MA
Park
M
M
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019898:Autocrine Communication; D002462:Cell Membrane / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D019814:Myristic Acid / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src); D012513:Sarcoma, Experimental / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D017228:Hepatocyte Growth Factor; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D008565:Membrane Proteins; D019814:Myristic Acid; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D016392:Proto-Oncogene Proteins pp60(c-src); C490897:Gab1 protein, mouse; C073597:TPR protein, human