Misregulation of receptor tyrosine kinase signaling in PKD

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DESCRIPTION (provided by applicant): Polycystic kidney disease (PKD) is a hereditary disease with a high prevalence and without a cure. PKD is characterized by numerous cysts within the kidneys of afflicted individuals. The cysts formed in PKD can greatly enlarge the kidneys while replacing the normal kidney structures, resulting in reduced kidney function and progression to end-stage renal disease, that can only be treated by lifelong dialysis or kidney transplants. As a disease that affects 1 in 800~1000 individuals, PKD is among the most common genetic disorders. In the United States, there are 600,000 individuals, and worldwide 12.5 million, with PKD [1]. Thus, PKD represents a major public health issue, and accounts for hundreds of millions (and perhaps over a billion) of dollars in health care costs, particularly for dialysis treatments and the cost of drugs that prevent transplant rejections, as well as the cost involved of decreased productivity and impaired quality of life of individuals with PKD. For all these reasons, it is of great importance to discover treatments that directly affect the molecular causes of PKD, and that will prevent the progression to end-stage renal disease and dialysis or transplantation. The mechanism of cyst formation in PKD is unknown: There are both autosomal dominant (ADPKD) and autosomal recessive (ARPKD) forms of PKD. ADPKD is more common and is caused by mutations in either the PKD1 or PKD2 genes, that encode Polycystin1 or Polycystin2, respectively [2]. Despite an enormous amount of intensive study in many laboratories, the mechanism of cyst formation remains incompletely understood. Recent progress in PKD research suggests the following potential mechanisms that could lead to cyst formation: (1) increased cell proliferation and/or apoptosis within epithelial tubules of the kidney; (2) enhanced fluid secretion into tubular lumina; (3) abnormality in the interaction of epithelial cells with their underlying basement membrane (cell-matrix adhesion) or with each other (cell-cell adhesion); (4) alterations in epithelial cell polarity; and (5) abnormal ciliary function. In our previous work we demonstrated a role of 31 integrin is cell-cell adhesion, in addition to cell-matrix adhesion. We have also demonstrated that the receptor tyrosine kinase c-Met requires interaction with 31 integrin for maximal activation in response to its ligand, HGF. In extending this work to PKD, we have found that 31 integrin is not properly localized to the plasma membrane, and c-Met is over-expressed in Pkd1-/- cells. This appears to be due to a failure to ubiqutinate c-Met after stimulation with HGF. Failure to ubquitinate c-Met is due to sequestration of the E3 ubiquitin ligase c-Cbl by 31 integrin in the Golgi apparatus. This grant will investigate the roles of c-Cbl, c-Met and protein glycosylation in the pathogenesis of PKD.