Functional relationships between hepatocyte growth factor receptor (HGF)/Met signaling and Ki-ras oncogenic mutation in colon carcinoma cells.
Published: 2005
Language: eng
Number of pages: 172
Description: Hepatocyte growth factor (HGF), the ligand for the Met tyrosine kinase receptor, is a multifunctional cytokine with a role in cell survival, migration, invasion, morphogenesis, angiogenesis, and cellular transformation. Deregulation of HGF/Met signaling has a role in many different types of cancer, including colon carcinoma. Ki-ras proto-oncogene belongs to a family of small, membrane-associated GTPases. Dominant activating mutations in Ki- ras are associated with tumorigenic transformation in many tissue types. Both Ki-ras mutation and Hepatocyte Growth Factor (HGF) receptor Met overexpression occur at high frequency in colon cancer. The model system used in these studies included the DLD-1 colon cancer cell line with a mutated Ki-ras allele, and the DKO-4 cell line generated from DLD-1, with its mutant Ki-ras allele inactivated by targeted disruption. These cell lines were transduced with cDNAs Met receptor. By increasing the duration of mitogen activated protein kinase (MAPK) activation and decreasing the frequency of apoptosis, Ki-ras mutations and HGF/Met signaling co-operate to enhance colon xenograft tumor growth rates  in vivo. Microarray global transcriptional profiling data demonstrate that transcriptional changes induced by Met receptor activation overlap with those induced by Ki-ras oncogene alone, indicating that the Ki-ras oncogene is the key transcriptional regulator in these colon carcinoma cells. Novel transcriptional targets of HGF/Met and Ki- ras signaling were identified by overlaying microarray and protein-protein interaction data in order to generate novel molecular interaction networks. Expression of a panel of modified Met receptors in DLD-1 cells demonstrates that Met downstream adaptor proteins Grb2 and Shc can play a role in tumor growth suppression through decreasing Gab1 protein levels. Gab1 is a large adaptor molecule that is crucial in regulating numerous biological processes downstream from the Met receptor. The regulation of Gab1 protein levels by Met signaling presents a novel mechanism for the regulation of tumor growth rate by HGF/Met signaling. Overall, the work presented here provides new insight into the interactions among different Met signaling pathways in the context of colon cancer progression.
Notes: Thesis (Ph.D.)--University of Toronto, 2005.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 66-06, Section: B, page: 2971.