Role of TSC Proteins in Regulating Cell Adhesion and Motility

摘要

The goal of this project was to define the molecular signaling mechanisms by which TSCI and TSC2 proteins regulate cell adhesion and motility as it relates to the genetic disorder tuberous sclerosis complex (TSC). The pathogenesis of TSC that develops due to the loss-of-function of tumor suppressors TSCI and TSC2 proteins represents an extremely complex and not fully understood interplay of deregulated cell functions. The neurological manifestations of TSC are related to brain lesions named tubers that have been defined as a neuronal migration disorder and occur due to aberrant neuronal motility during brain development. As a result of aberrant neuronal motility affected individuals may suffer from seizures mental retardation and autism. Thus TSC represents a major cause of developmental disorders and epilepsy in the pediatric population. The central hypothesis of this proposal was: TSC proteins regulate cell adhesion and motility and loss of either TSCI or TSC2 function alters cell adhesion and induces aberrant motility promoting the pathological conditions associated with TSC Pl3K and small GTPases RhoA and RacI respectively serve as the upstream modulator and downstream effectors of TSCI and TSC2 proteins. The significance of this work relates to better understanding of the molecular and cellular mechanisms of the pathobiology of TSC such that new therapeutic targets can be identified to treat this devastating disease.