ErbB Receptor-induced Activation of Stat Transcription Factors Is Mediated by Src Tyrosine Kinases

Abstract

Epidermal growth factor (EGF) binding to its receptor, ErbB1, triggers various signal transduction pathways, one of which leads to the activation of signal transducer and activator of transcription (Stat) factors. The mechanism underlying ErbB1-induced Stat activation and whether Stats are downstream targets of other ErbB receptors have not been explored. In this report we show that ErbB2, ErbB3, and ErbB4 do not potentiate Stat5 phosphorylation by EGF. However, neu differentiation factor-induced heterodimers of ErbB2 and ErbB4 activated Stat5. In A431 cells, Stat1, Stat3, and Stat5, were constitutively complexed with ErbB1 and rapidly phosphorylated on tyrosine in response to EGF. Neither mutation of the conserved tyrosine residue (Tyr 694 ) nor inactivation of the Stat5a SH2 domain disrupted this association. However, an intact SH2 domain was necessary for EGF-induced Stat5a phosphorylation. In contrast to prolactin, which induced only Tyr 694 phosphorylation of Stat5a, EGF promoted phosphorylation on Tyr 694 and additional tyrosine residue(s). Janus kinases (Jaks) were also constitutively associated with ErbB receptors and were phosphorylated in response to EGF-related ligands. However, we provide evidence that EGF-and neu differentiation factor-induced Stat activation are dependent on Src but not Jak kinases. Upon EGF stimulation, c-Src was rapidly recruited to Stat/ ErbB receptor complexes. Pharmacological Src kinase inhibitors and a dominant negative c-Src ablated both Stat and Jak tyrosine phosphorylation. However, dominant negative Jaks did not affect EGF-induced Stat phosphorylation. Taken together, the experiments establish two independent roles for Src kinases: (i) key molecules in ErbB receptor-mediated Stat signaling and (ii) potential upstream regulators of Jak kinases.The ErbB family of receptor tyrosine kinases, consisting of the epidermal growth factor (EGF) 1 receptor ErbB1, ErbB2/ Neu, ErbB3, and ErbB4, binds a large group of ligands, the EGF-related peptides (1, 2). Upon ligand-induced dimerization, the receptors autophosphorylate on specific tyrosine residues in their cytoplasmic tails. These residues provide docking sites for phosphotyrosine binding, cytoplasmic signaling molecules that activate numerous intracellular signaling pathways. In some cases, for example the mitogen-activated protein (MAP) kinase pathway, the important intermediates in the signaling cascade have been well described (3). Receptor tyrosine kinasemediated activation of signal transducer and activators of transcription (Stat) proteins, however, is less well understood.Stats were initially identified as a family of transcription factors activated by engagement of interferon (IFN) and cytokine receptors, which lack intrinsic kinase activity and depend upon the receptor-associated Janus kinases (Jaks) to transduce signals. Cytokine receptor oligomerization brings the Jaks into juxtaposition, leading to their cross-phosphorylation and activation. Jaks in turn phosphorylate receptors on tyrosine residues, thereby providing...

Constitutive activation of STAT3 and STAT5 is present in the majority of nasopharyngeal carcinoma and correlates with better prognosis

“…We also noted that constitutively activated STAT3 and STAT5 frequently coexisted in the same specimen. It has been shown that different STATs can be activated by the same ligand and/or intracellular tyrosine kinase (Ruff-Jamison et al, 1994;Carlesso et al, 1996;Olayioye et al, 1999). Simultaneously persistent STATs activation is also noted in a variety of human cancers (Turkson and Jove, 2000).…”

Clinical relevance of ErbB-2/HER2 nuclear expression in breast cancer

“…Human epidermal growth factor receptor 2 (ErbB-2/HER2), one of the members of the ErbB family of membrane receptor tyrosine kinases, is a major player in the breast cancer scenario [1]. Membrane ErbB-2 (MembErbB-2) overexpression is associated with poor clinical outcome [2].…”

“…However, a significant percentage of tumors display primary or acquired trastuzumab resistance [5]. Notably, the dogma of ErbB-2 action as a membrane tyrosine kinase which induces the activation of mitogenic signaling pathways to promote breast cancer growth [1], has been challenged by the demonstration that MembErbB-2 migrates to the nuclear compartment, where it acts as a transcription factor (TF) [6]. Up to date, cyclooxygenase-2 (COX-2) gene is the only one whose expression has been shown to be modulated through the role of ErbB-2 as a TF in mammary tumor cells [6].…”

EGF receptor‐mediated, c‐Src‐dependent, activation of Stat5b is downregulated in mitogenically responsive hepatocytes

“…Stat5a and Stat5b in hematopoietic cells seem to promote growth, inhibit apoptosis, and may be involved in malignant transformation (Matsumura et al, 1999;Nosaka et al, 1999;Demoulin et al, 2000), and are also essential mediators of the effects of prolactin (PRL) and growth hormone (GH) as well as IL-2 and other cytokines (Groner and Gouilleux, 1995;Grimley et al, 1999;Moriggl et al, 1999;Herrington et al, 2000;Lin and Leonard, 2000). However, although STAT proteins in some cells have been found to be phosphorylated and activated in response to growth factors, including EGF (Ruff-Jamison et al, 1993Richer et al, 1998;Guren et al, 1999;Luetteke et al, 1999;Olayioye et al, 1999), PDGF (Valgeirsdottir et al, 1998;Sachsenmaier et al, 1999), and VEGF (Bartoli et al, 2000), their exact function in receptor tyrosine kinase signaling has not been defined, and the role of STAT proteins in EGF receptor-mediated mitogenic mechanisms is not known.…”