ephrinB1 signals from the cell surface to the nucleus by recruitment of STAT3

Abstract

The Eph (erythropoietin-producing hepatoma) family of receptor tyrosine kinases and their membrane-bound ligands, the ephrins, have been implicated in regulating cell adhesion and migration during development by mediating cell-to-cell signaling events. The transmembrane ephrinB (Eph receptor interactor B) protein is a bidirectional signaling molecule that sends a forward signal through the activation of its cognate receptor tyrosine kinase, residing on another cell. A reverse signal can be transduced into the ephrinBexpressing cell via tyrosine phosphorylation of its conserved Cterminal cytoplasmic domain. Although some insight has been gained regarding how ephrinB may send signals affecting cytoskeletal components, little is known about how ephrinB1 reverse signaling affects transcriptional processes. Here we report that signal transducer and activator of transcription 3 (STAT3) can interact with ephrinB1 in a phosphorylation-dependent manner that leads to enhanced activation of STAT3 transcriptional activity. This activity depends on the tyrosine kinase Jak2, and two tyrosines within the intracellular domain of ephrinB1 are critical for the association with STAT3 and its activation. The recruitment of STAT3 to ephrinB1, and its resulting Jak2-dependent activation and transcription of reporter targets, reveals a signaling pathway from ephrinB1 to the nucleus.FGF receptor ͉ Eph receptor ͉ neuroepithelial cells ͉ tyrosine phosphorylation ͉ Jak2 M embrane-anchored ephrinB (erythropoietin-producing hepatoma interactor B) proteins are ligands for EphB receptors and have been involved in many biological processes such as cell adhesion, neural crest migration, brain segmentation, and vasculogenesis (1-3). Upon cell-to-cell contact, ephrinB1 not only sends a forward signal through the activation of its cognate receptor, but it also rapidly undergoes tyrosine phosphorylation at the C terminus and recruits the adaptor protein growth-factor-receptor-bound protein 4 (Grb4)/Nck adaptor protein 2 (Nck2), resulting in an increase of focal adhesion kinase (FAK) catalytic activity as well as cell rounding (4). In addition, the C-terminal PDZ-binding motif of ephrinB1 is able to mediate reverse signaling by recruitment of PDZ-RGS3, a GTP exchange factor that regulates the migration of cerebellar granule cells (5). Moreover, it has been reported that ephrinB1 signals through its intracellular domain to control retinal progenitor cell movement into the eye field by interacting with the scaffold protein Dishevelled (6). Thus, several signaling molecules have been identified to transmit reverse signaling of ephrinB1 by either phosphorylation-dependent or -independent means. ephrinB1 can be phosphorylated in response to binding a cognate Eph receptor (7,8) or the tight junction protein Claudin (9) or in response to FGF receptor activation (10). Among the six tyrosine residues present in the intracellular domain of ephrinB1, one resides in a well conserved YXXQ motif at the C terminus and is rapidly phosphorylated upon engagement of t...

LIM Domain Only 4 (LMO4) Regulates Calcium-Induced Calcium Release and Synaptic Plasticity in the Hippocampus

“…LMO4 is a small protein (165 aa) that contains two protein-interacting LIM domains. LMO4 serves not only as a cofactor of many transcription factors (Manetopoulos et al, 2003;Kashani et al, 2006;Schock et al, 2008), but also interacts with transmembrane receptors to modulate their signaling (Novotny-Diermayr et al, 2005;Bong et al, 2007). Whether LMO4 couples signals from membrane receptors to changes in gene expression is not known, although we showed that LMO4 is present in the cytoplasm and nucleus, and translocates from the cytoplasm to the nucleus in response to extracellular stimuli (Chen et al, 2007a).…”

EphB6 receptor significantly alters invasiveness and other phenotypic characteristics of human breast carcinoma cells

“…In light of these reports, it is not unreasonable to believe that higher levels of TIMP2 and lower levels of TIMP3 transcripts are mediators of similar phenotypic effects in EphB6-transfected MDA-MB-231 cells. The mechanism of MMP and TIMP transcriptional regulation is not clear; however, it has been shown that Eph receptors (Lai et al, 2004) and ephrin ligands (Bong et al, 2007) can transduce signals to the nucleus through the Jak/STAT pathway. In addition, EphB6 is capable of suppressing signaling through the JNK pathway in T-cell development following stimulation with ephrinB1 (Freywald et al, 2003).…”

DNA damage-induced ephrin-B2 reverse signaling promotes chemoresistance and drives EMT in colorectal carcinoma harboring mutant p53

“…The bidirectional signaling molecule ephrin-B2 becomes clustered upon interaction with its Eph receptor 37 and activates key signaling moieties such as Src, 28 PDGFRβ, 37 VEGFR2, 38 STAT3, 39 and many more. Until date, only one study has reported the involvement of Eph-ephrin signaling in conferring radioresistance, but the mechanism is poorly understood.…”