Activation of phosphoinositide 3-kinase by the NBS1 DNA repair protein through a novel activation motif.

Abstract

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.

• Authors: Yen-Chung Chen, Hsiu-Yin Chiang, Muh-Hwa Yang, Po-Min Chen, Shyue-Yih Chang, Shu-Chun Teng, Bart Vanhaesebroeck, Kou-Juey Wu
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 86 Issue 4 Pg. 401-12 (Apr 2008) ISSN: 0946-2716 [Print] Germany
• PMID: 18270679 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• NBN protein, human
• Nuclear Proteins
• Protein Subunits
• Recombinant Fusion Proteins
• Phosphatidylinositol 3-Kinases

Topics

• Amino Acid Sequence
• Animals
• Cell Cycle Proteins (genetics, metabolism)
• Cell Line
• Enzyme Activation
• Humans
• Molecular Sequence Data
• Nuclear Proteins (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Protein Structure, Tertiary
• Protein Subunits (genetics, metabolism)
• Rats
• Recombinant Fusion Proteins (genetics, metabolism)
• Sequence Alignment