Cowden syndrome-related mutations in PTEN associate with enhanced proteasome activity.

[cowden syndrome]

Germline mutations in PTEN have been described in a spectrum of syndromes that are collectively known as PTEN hamartoma tumor syndrome (PHTS ). In addition to being mutated in the germline in PHTS , somatic loss -of-function PTEN mutations are seen in a wide range of sporadic human tumors . Here , we show evidence of upregulated proteasome activity in PHTS-derived lymphoblasts , Pten knock-in mice and cell lines expressing missense and nonsense PTEN mutations . Notably , elevated nuclear proteasome activity occurred in cells expressing the nuclear mislocalized PTEN -K 62 R mutant , whereas elevated cytosolic proteasome activity was observed in cells expressing the cytosolic-predominant mutant PTEN (M 3 M 4 and C 136 R ). Treatment with proteasome inhibitor MG-132 was able to restore both nonsense and missense mutant PTEN protein levels in vitro . PHTS patients with destabilizing PTEN mutations and proteasome hyperactivity are more susceptible to develop neurologic symptoms such as mental retardation and autism than mutation -positive patients with normal proteasome activity . A detailed molecular and functional analysis shows that PTEN mutants most likely cause proteasome hyperactivity via 2 different mechanisms , namely , induction of proteotoxic stress and loss of protein phosphatase activity . These results provide novel insights into the cellular functions of PTEN and reveal molecular mechanisms whereby PTEN mutations increase proteasome activity and lead to neurologic phenotypes .