The Serine Protease HtrA1 Specifically Interacts and Degrades the Tuberous Sclerosis Complex 2 Protein

Abstract

Hamartin and tuberin are products of the tumor suppressor genes TSC1 and TSC2, respectively. Mutations affecting either gene result in the tuberous sclerosis syndrome, a neurologic genetic disorder characterized by the formation of multiple benign tumors or hamartomas. In this study, we report the identification of TSC2, but not TSC1, as a substrate of HtrA1, a member of the human HtrA family proteins of serine proteases. We show the direct interaction and colocalization in the cytoplasm of HtrA1 and TSC2 and that HtrA1 cleaves TSC2 both in vitro and in vivo. Finally, we show that alterations in HtrA1 expression cause modifications in phosphorylation status of two downstream targets of TSC2: 4E-BP1 and S6K. Our data suggest that, under particular physiologic or pathologic conditions, HtrA1 degrades TSC2 and activates the downstream targets. Considering that HtrA1 levels are significantly increased during embryogenesis, we speculate that one of the targets of HtrA1 activity during fetal development is the TSC2-TSC1 pathway. Mol Cancer Res; 8(9); 1248-60. ©2010 AACR.

DNA methylation changes in the placenta are associated with fetal manganese exposure

“…Further, additional genes were associated with the development of or risk for various neurological disorders, including autism ( ROBO3 53 , SYN3 and GRIK4 68 ), attention deficit hyperactivity disorder ( ISL1 69 ), Tourette’s syndrome ( SLITRK1 70 ), schizophrenia ( NEUROD1 55 and CYFIP1 71 ), and Alzheimer’s disease ( NQO1 72 and FKBP1B 73 ). Several genes on this list, including G2E3 74 , GNAS 75 , and TSC2 76 , are crucial for normal embryonic development. VEGF 77 is important for angiogenesis, a key placental function; CYR61 78 has been implicated in preeclampsia; and two others of the identified genes are involved in trophoblast differentiation and placental development ( PARP1 79 and NEUROD1 80 ).…”

Structural insights into the activation mechanisms of human HtrA serine proteases

“…Results of studies on cancer cell lines and animal models revealed that downregulation of HtrA1 contributed to survival of cancer cells, increased cell migration and metastasis while overexpression of HtrA1 inhibited cell proliferation in vitro and tumor outgrowth in vivo [13e15,28]. It has also been shown that HtrA1 interacts with and degrades tuberin, product of the tumor suppressor TSC2 gene; mutations in this gene are linked to neurologic disorder characterized by formation of multiple benign tumors [29].…”

Determinants of amyloid fibril degradation by the PDZ protease HTRA1

“…Secreted HTRA1 is involved in the homeostasis of the extracellular matrix [9][10][11][12][13][14] , and intracellular HTRA1 localizes to the cytoplasm, microtubules and nucleus 8,15,16 . Microtubule-associated HTRA1 degrades tubulins, thereby inhibiting cell migration 8,17 .…”