TI - Tuberin phosphorylation regulates its interaction with hamartin . Two proteins involved in tuberous sclerosis . AB - Hamartin and tuberin are products of the tumor suppressor genes , TSC1 and TSC2 , respectively . When mutated , a characteristic spectrum of tumor-like growths develop resulting in the syndrome of tuberous sclerosis complex . The phenotypes associated with TSC1 and TSC2 mutations are largely indistinguishable suggesting a common biochemical pathway . Indeed , hamartin and tuberin have been shown to interact stably in vitro and in vivo . Factors that regulate their interaction are likely critical to the understanding of disease pathogenesis . In this study , we showed that tuberin is phosphorylated at serine and tyrosine residues in response to serum and other factors , and it undergoes serial phosphorylation that can be detected by differences in electrophoretic mobilities . A disease-related TSC2 mutation (Y1571H) nearly abolished tuberin phosphorylation when stimulated with pervanadate . Expression of this mutant tuberin caused a marked reduction in TSC1-TSC2 interaction compared with wild-type protein and significantly curtailed the growth inhibitory effects of tuberin when overexpressed in COS1 cells , consistent with a loss of function mutation . Examination of a second pathologic mutation , P1675L , revealed a similar relationship between limited phosphorylation and reduced interaction with hamartin . Our data show for the first time that 1 ) tuberin is phosphorylated at tyrosine and serine residues , 2 ) TSC1-TSC2 interaction is regulated by tuberin phosphorylation , and 3 ) defective phosphorylation of tuberin is associated with loss of its tumor suppressor activity . These findings suggest that phosphorylation may be a key regulatory mechanism controlling TSC1-TSC2 function .