Activation of phosphoinositide 3-kinase by the NBS1 DNA repair protein through a novel activation motif.
Class IA phosphoinositide 3-kinases (PI 3-kinases) are key signaling components downstream of tyrosine kinases and Ras, regulating many different cellular functions and contributing to tumorigenesis. Class IA PI 3-kinases are heterodimers comprised of a p85 regulatory and a p110 catalytic subunit. Nijmegen breakage syndrome (NBS) is a chromosomal instability syndrome associated with cancer predisposition, radiosensitivity, microcephaly, and growth retardation. The NBS gene product p95 (also known as NBS1) is part of the Mre11-Rad50-Nbs1 complex, a central player associated with double-strand break repair. We previously demonstrated that NBS1 overexpression induces transformation through activation of PI 3-kinase/Akt. In this study, we show that NBS1 directly interacts, through a highly conserved C-terminal motif (aa 653-669) of NBS1, with the N-terminal domain (aa 1-108) of the p110alpha catalytic subunit of PI 3-kinase, and stimulates PI 3-kinase activity. Mutations of different regions of the conserved motif abolish the ability of NBS1 to activate PI 3-kinase in vitro and in vivo. Co-expression of NBS1/p110alpha/p-Akt is observed in certain percentage of head and neck cancer patient samples. These results demonstrate that NBS1 can function as an adaptor/activator of p110alpha PI 3-kinase through a novel activation motif, consistent with its possible role in cell transformation and tumorigenesis.
Chen
Yen-Chung
YC
Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No.155, Li-Nong St., Sec.2, Peitou, Taipei 112, Taiwan.
Chiang
Hsiu-Yin
HY
Yang
Muh-Hwa
MH
Chen
Po-Min
PM
Chang
Shyue-Yih
SY
Teng
Shu-Chun
SC
Vanhaesebroeck
Bart
B
Wu
Kou-Juey
KJ
D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D019869:Phosphatidylinositol 3-Kinases