Figure 2. Signaling by NEDD9 relevant to the pathogenesis of BCR-ABL positive malignancies.

NEDD9 co-localizes and interacts with BCR-ABL and its adaptor protein CRKL [49, 51], likely serving as a hub [50] for an assembly of protein complexes between CRKL and its downstream effectors: SYK [53], C3G [42], BRAF, SAPK, JNK [47], and STAT5 [52]. SRC family kinase Syk induces the PI3K/AKT/MTOR pathway enhancing cell survival [117]; activation of the RAS/RAF/MEK/ERK pathway drives cell proliferation; transcription factors STAT5 and JNK activate transcription of a large number of target genes [47]. Signaling through B-cell receptor, chemokine receptor and/or integrins lead to NEDD9 activation by the FAK/SRC/PXN complex; active NEDD9, in turn, helps to support continuous activation of FAK and SRC [56]. Phosphorylated NEDD9 binds CRKL and promotes migration and chemotaxis through activation of WASP/ARP2/3 signaling (reviewed in [4, 54]). ABL-mediated tyrosine phosphorylation of NEDD9 and binding of C3G leads to activation of Rap1 and migration/chemotaxis of lymphoid cells [41]. ARP2/3 - protein complex regulating actin cytoskeleton; WASP - Wiskott-Aldrich syndrome family protein; CRKL - adaptor protein encoded by V-crk avian sarcoma virus CT10 oncogene homolog; PXN – paxillin; FAK – focal adhesion kinase; SRC – (short for sarcoma), proto-oncogene non-receptor tyrosine kinase Src; RAF – family of serine/threonine protein kinases controlling cell proliferation; activation of RAF kinases requires interaction with RAS-GTPases; SYK - spleen tyrosine kinase; JNK – c-Jun N-terminal kinase; SAPK – stress-activated protein kinase; STAT – signal transducers and activators of transcription.