Tyrosine Docking Sites of the Rat Prolactin Receptor Required for Association and Activation of Stat5

Pezet, Alain; Ferrag, Fatima; Kelly, Paul A.; Edery, Marc

doi:10.1074/jbc.272.40.25043

Cited by 88 publications

(59 citation statements)

References 49 publications

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“…Further receptor systems in which a tyrosine-based STAT5 recruitment has been shown include the growth hormone receptor (40 -42), erythropoietin receptor (43)(44)(45) and the IL-2 receptor ␤-chain (46). Particularly, the similarity with a STAT5-binding motif within the erythropoietin receptor (Tyr 431 ) LKYLYLVVS is remarkable (47). Interestingly, the double tyrosine motif is not conserved between man and mouse.…”

Section: Discussionmentioning

confidence: 95%

Box 2 Region of the Oncostatin M Receptor Determines Specificity for Recruitment of Janus Kinases and STAT5 Activation

Hintzen

Evers

Lippok

et al. 2008

Journal of Biological Chemistry

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Human and murine oncostatin M (OSM) induce their bioactivities through a heterodimeric receptor complex consisting of gp130 and the OSM receptor (OSMR), which initiates a signaling pathway involving Janus kinases (JAKs) and transcription factors of the signal transducers and activators of transcription (STAT) family. In contrast to the signal transducing receptor subunit gp130, the OSMR allows strong activation of STAT5B. The underlying molecular mechanism, however, remained unclear. Here we demonstrate that the human and murine OSM receptors use distinct mechanisms for STAT5B activation. The human receptor contains a STAT5B recruiting tyrosine motif (Tyr 837 /Tyr 839 ) C-terminal to the box 1/2 region, which is absent in the mouse receptor. In contrast, the murine receptor initiates STAT5 activation directly via the receptor bound Janus kinases. Intriguingly, the murine receptor preferentially recruits JAK2, whereas the human receptor seems to have a higher affinity for JAK1. We identify a single amino acid (Phe 820 ) in the human receptor that is responsible for this preference. Exchange by the murine counterpart (Cys 815 ) allows recruitment of JAK2 by the human receptor and consequently activation of STAT5B independently of receptor tyrosine motifs. STAT5B interacts directly with JAK2 only in response to activation of the murine OSMR or the mutated human OSMR. Additionally, we show that OSM-induced STAT1 phosphorylation occurs independently of receptor tyrosine motifs and is mediated directly by Janus kinases, whereas the two C-terminally located tyrosine residues Tyr 917 /Tyr 945 of the OSMR are crucial for STAT3 activation.

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Section: Discussionmentioning

confidence: 95%

Box 2 Region of the Oncostatin M Receptor Determines Specificity for Recruitment of Janus Kinases and STAT5 Activation

Hintzen

Evers

Lippok

et al. 2008

Journal of Biological Chemistry

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“…These results suggest that GH-dependent activation of STAT5 proteins requires binding of the STAT to one or more phosphorylated tyrosines in the cytoplasmic domain of GH receptor. A similar requirement of multiple phosphorylated tyrosine(s) in the receptor for maximal activation of STAT5 has been demonstrated for EPO, PRL, IL-2, IL-5 and granulocyte-macrophage colonystimulating factor (Damen et al, 1995;Fujii et al, 1995;Itoh et al, 1998;Pezet et al, 1997;Quelle et al, 1996;van Dijk et al, 1997).…”

Section: Mechanism Of Activation Of Stat Proteins By Ghmentioning

confidence: 95%

The role of STAT proteins in growth hormone signaling

et al. 2000

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Growth hormone (GH) has long been known to be the body's primary regulator of body growth and a regulator of metabolism, yet the mechanisms by which GH regulates the transcription of speci®c genes required for these processes are just now being delineated. GH binding to its receptor recruits and activates the receptor-associated JAK2 that in turn phosphorylates tyrosines within itself and the GH receptor. These tyrosines form binding sites for a number of signaling proteins, including members of the family of signal transducers and activators of transcription (STAT). Among the known signaling molecules for GH, STAT proteins play a particularly prominent role in the regulation of gene transcription. This paper will review what is currently understood about which STAT proteins are regulated by GH, how they are regulated by GH, the GH-dependent genes they regulate, and discuss current theories about how GH-activated STAT signaling is regulated. Particular attention will be given to the novel role that STAT5 plays in sexually dimorphic gene expression in the liver as determined by the secretory pattern of GH and the role of STAT5 in body growth.

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“…Furthermore, we determined that this tyrosine also regulates the activation of Stat5 (32). In addition, other studies have shown that the C-terminal tyrosine of the receptor regulates Stat5 recruitment to the PRLR (38). The association of SHP-2 or Stat5 to the FIG.…”

Section: Discussionmentioning

confidence: 99%

Recruitment of the Protein-tyrosine Phosphatase SHP-2 to the C-terminal Tyrosine of the Prolactin Receptor and to the Adaptor Protein Gab2

Ali¹,

Ali

2000

Journal of Biological Chemistry

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The protein-tyrosine phosphatase SHP-2 modulates signaling events through receptor tyrosine kinases and cytokine receptors including the receptor for prolactin (PRLR). Here we investigated mechanisms of SHP-2 recruitment within the PRLR signaling complex. Using SHP-2 and PRLR immunoprecipitation studies in 293 cells and in the mouse mammary epithelial cell line HC11, we found that SHP-2 co-immunoprecipitates with the PRLR and that the C-terminal tyrosine of the PRLR plays a regulatory role in both the tyrosine phosphorylation and the recruitment of SHP-2. Our results further indicate that SHP-2 association to the PRLR occurs via the C-terminal SH2 domain of the phosphatase. In addition, we determined that the newly identified adaptor protein Gab2, but not Gab1, is specifically tyrosine phosphorylated and is able to recruit SHP-2 and phosphatidyinositol 3-kinase in response to PRLR activation. Together, these studies suggest the presence of dual recruitment sites for SHP-2; the first is to the C-terminal tyrosine of the PRLR and the second is to the adaptor protein Gab2.

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Tyrosine Docking Sites of the Rat Prolactin Receptor Required for Association and Activation of Stat5

Cited by 88 publications

References 49 publications

Box 2 Region of the Oncostatin M Receptor Determines Specificity for Recruitment of Janus Kinases and STAT5 Activation

Box 2 Region of the Oncostatin M Receptor Determines Specificity for Recruitment of Janus Kinases and STAT5 Activation

The role of STAT proteins in growth hormone signaling

Recruitment of the Protein-tyrosine Phosphatase SHP-2 to the C-terminal Tyrosine of the Prolactin Receptor and to the Adaptor Protein Gab2

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