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 cyto plasmic domain of the Met receptor, producing a cytosolic, constitutively a ctivated tyrosine kinase. Although both the Met receptor and the Tpr-Met on coprotein associate with the same substrates, activating mutations of the M et receptor in hereditary papillary; renal carcinomas have different signal ing requirements for transformation than Tpr-Met. This suggests differentia l activation of membrane-localized pathways by oncogenic forms of the membr ane-bound Met receptor but not by the cytoplasmic Tpr-Met oncoprotein. To e stablish which pathways might be differentially regulated, we have localize d the constitutively activated Tpr-Met oncoprotein to the membrane using th e c-src myristoylation signal. Membrane localization enhances cellular tran sformation, focus formation, and anchorage-independent growth and induces t umors 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 membran e-targeted form of PI3'K is sufficient to enhance HA production. Furthermor e, the multisubstrate adapter protein Gab-1, which couples the Met receptor with PI3'K enhances Met receptor-dependent IU synthesis in a PI3'K-depende nt manner. These results provide a positive huh to a role for HA and CD44 i n Met receptor-mediated oncogenesis and implicate PI3'K in these events.