EphB2 receptor forward signaling controls cortical growth cone collapse via Nck and Pak

Abstract

EphB receptors and their ephrinB ligands transduce bidirectional signals that mediate contact-dependent axon guidance primarily by promoting growth cone repulsion. However, how EphB receptor-mediated forward signaling induces axonal repulsion remains poorly understood. Here, we identify Nck and Pak proteins as essential forward signaling components of EphB2-dependent growth cone collapse in cortical neurons. We show that kinase-active EphB2 binds to Pak and promotes growth cone repulsion via Pak kinase activity, Pak-Nck binding, RhoA signaling and endocytosis. However, Pak’s function in this context appears to be independent of Rac/Cdc42-GTP, consistent with the absence of Rac-GTP production after ephrinB treatment of cortical neurons. Taken together, our findings suggest that ephrinB-activated EphB2 receptors recruit a novel Nck/Pak signaling complex to mediate repulsive cortical growth cone guidance, which may be relevant for EphB forward signaling-dependent axon guidance in vivo.

Kallikrein‐8 inhibition attenuates Alzheimer's disease pathology in mice

“…For instance in the amygdala, EPHB2 cleavage by KLK8 induces the expression of FK506-binding protein-5 (FKBP5), which in turn regulates glucocorticoid receptor sensitivity and provokes anxiety [3]. EPHB2 signaling via trans-cellular communication with ephrin B2 ligand (EFNB2) is further of particular relevance for neuronal plasticity, as it coordinates axonal guidance [4] and controls synaptogenesis [5]. EPHB2 signal transduction is also known to induce angiogenesis [6] and autophagy [7,8] under neoplastic conditions.…”

Phosphatase of Regenerating Liver 3 (PRL3) Provokes a Tyrosine Phosphoproteome to Drive Prometastatic Signal Transduction

“…Adding to the relevance of Nck2 and Rac1 activation in the PRL3 cells is the exclusive presence of phosphopeptides representing pTyr-588 and -594 of Ephrin receptor A2 (EphA2), phosphorylation sites known to coordinate the Nck adaptor proteins as well as Vav2/3 Rac1-GEFs (32,87). Though the functional relevance of pTyr792 of EphB3 and pTyr774 of EphB4, remains unclear, phosphorylated B-type Eph-receptors also mediate Nck2 association toward the cytoskeletal re-organization observed during ephrinB forward and reverse signaling (32,83,88). Finally, evidence suggest- Graphical model depicting phosphoproteomic data present within the PRL3 dataset that supports a mechanism by which PRL3 potentiates pro-metastatic signal transduction by exploiting "oncogenic" Src kinase activity.…”

EphB receptor forward signaling regulates area-specific reciprocal thalamic and cortical axon pathfinding

“…The Eph family of receptor tyrosine kinases is divided into two subgroups: the A class (A1-A8 and A10) and the B class (B1-B4 and B6), based largely on their similarity and binding preferences for ephrinA and ephrinB ligands (17). The high affinity interaction between Ephs and ephrins, typically upon cell-cell contact, triggers both forward and reverse signaling events that promote reorganization of the F-actin cytoskeleton (16,19,20), a cellular process critical for axon turning, outgrowth, and cell migration.…”