title: Phosphorylation of P-Rex1 at serine 1169 participates in IGF-1R signaling in breast cancer cells.
abstract: Former reports demonstrated that P-Rex, a Rac guanine nucleotide exchange factor (GEF), participated in signaling upon activation of the ErbB receptor tyrosine kinases (RTKs). Activation of ErbB receptors turned on a phosphorylation/dephosphorylation cycle of P-Rex in which stimulation of serine(1169) phosphorylation played a critical role in the activation of this GEF. This precedent raised the important question of whether this P-Rex1 activation mechanism was restricted to ErbB receptors or could represent a general signaling event shared by several RTKs. To explore that possibility the effect of activation of distinct RTKs on the phosphorylation of P-Rex1 at serine(1169) was analyzed. Here we report that IGF-1 and FGF receptors activate serine(1169) phosphorylation of P-Rex1. P-Rex1 phosphorylation was required for IGF-1-induced up-regulation of Rac activity and cell proliferation. Moreover, IGF-1-induced adhesion was impaired in MCF7 breast cancer cells by knocking down P-Rex1. These results demonstrate that phosphorylation P-Rex1 at S(1169) represents a mechanism of activation of P-Rex1 common to multiple RTKs. We suggest that P-Rex proteins may act as novel and important transducers of pro-oncogenic signals that emanate from RTKs, and could even participate in other biological responses, such as metabolic control, which are not strictly related to the proliferation effects of RTKs.
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Montero
authors.forename: Samuel
authors.initials: S
authors.lastname: Seoane
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D061251:Primary Cell Culture; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C453280:PREX1 protein, human; D017468:Receptors, Fibroblast Growth Factor; D012694:Serine; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D020744:rac GTP-Binding Proteins
keywords: Breast cancer; FGF; FGFR; GAP; GEF; GTPase activating proteins; IGF-1; IGF-1R; NRG; P-Rex; PI3K; PIP(3); RTKs; Tyrosine kinases; fibroblast growth factor; fibroblast growth factor receptor; guanine nucleotide exchange factor; insulin-like growth factor-1; insulin-like growth factor-1 receptor; mTOR; mammalian target of rapamycin; neuregulin; phosphatidylinositol (3,4,5)-trisphosphate; phosphoinositide 3-kinase; receptor tyrosine kinases