A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling

Authors
García Martínez, José Manuel; Calcabrini, Annarica; Gonzalez, Lorena; Martín Forero, Esther; Agulló Ortuño, María Teresa; Simon, Valérie; Watkin, Harriet; Anderson, Steve M.; Roche, Serge; Martin Pérez, Jorge
Publication Year
2010
Language
English
Format
article
Status
Published version
Description
The cytokine prolactin (PRL) plays important roles in the proliferation and differentiation of the mammary gland and it has been implicated in tumorigenesis. The prolactin receptor (PRLR) is devoid of catalytic activity and its mitogenic response is controlled by cytoplasmic tyrosine kinases of the Src (SFK) and Jak families. How PRLR uses these kinases for signaling is not well understood. Previous studies indicated that PRLR-induced Jak2 activation does not require SFK catalytic activity in favor of separate signaling operating on this cellular response. Here we show that, nevertheless, PRLR requires Src-SH2 and -SH3 domains for Jak2 signaling. In W53 lymphoid cells, conditional expression of two c-Src non-catalytic mutants, either SrcK295M/Y527F or Src∆K, whose SH3 and SH2 domains are exposed, controls Jak2/Stat5 activation by recruiting Jak2, avoiding its activation by endogenous active SFK. In contrast, the kinase inactive SrcK295M mutant, with inaccessible SH3 and SH2 domains, does not. Furthermore, all three mutants attenuate PRLR-induced Akt and p70S6K activation. Accordingly, PRLR-induced Jak2/Stat5 signaling is inhibited in MCF7 breast cancer cells by Src depletion, expression of SrcK295M/Y527F or active Src harboring an inactive SH2 (SrcR175L) or SH3 domain (SrcW118A). Finally, Jak2/Stat5 pathway is also reduced in Src−/− mice mammary glands. We thus conclude that, in addition to Akt and p70S6K, SFK regulate PRLR-induced Jak2 signaling through a kinase-independent mechanism.
Fil: García Martínez, José Manuel. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; España
Fil: Calcabrini, Annarica. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; España
Fil: Gonzalez, Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Autónoma de Madrid; España
Fil: Martín Forero, Esther. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; España
Fil: Agulló Ortuño, María Teresa. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; España
Fil: Simon, Valérie. Centre de Recherche de Biochimie Macromoléculaire; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Watkin, Harriet. University of Colorado Health Sciences Center; Estados Unidos
Fil: Anderson, Steve M.. University of Colorado Health Sciences Center; Estados Unidos
Fil: Roche, Serge. Centre de Recherche de Biochimie Macromoléculaire; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Martin Pérez, Jorge. Universidad Autónoma de Madrid; España. Consejo Superior de Investigaciones Cientificas; España
Subject
PROLACTIN
SRC FAMILY KINASES
SRC SCAFFOLD FUNCTIONS
JAK2
STA5
AKT
ERK1/2
CELL PROLIFERATION
Bioquímica y Biología Molecular
Ciencias Biológicas
CIENCIAS NATURALES Y EXACTAS
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/18220