Reverse signaling by Ephrin B
Ephrin receptors and Ephrins
are both membrane bound, and following their interaction and clustering, each can
transduce signals that regulate cell responses .
Ephrin receptors activate reverse signaling through their
Ephrin ligands .
Ephrin-B receptors induce
Ephrin-B tyrosine phosphorylation. Src family kinases are
responsible for Ephrin-B phosphorylation, but this
activation is transient. At later time points Ephrin-B
ligands recruit phosphotyrosine Phosphatase protein-tyrosine phosphatase PTPL1
(FAP-1) to the membrane and become dephosphorylated. This is
suggested the presence of a switch mechanism that allows
Ephrin-B ligands to shift from fast
phosphotyrosine/Src-dependent signaling to delayed signaling .
Tyrosine phosphorylation of Ephrin-B
results in binding of the NCK adaptor protein
2 (Grb4), which links Ephrin-B
to a vast signaling network that modifies cell morphology through reorganization of
Actin cytoskeleton .
Grb4 could associate with a number of signaling
molecules. It can bind to G-factor Son of sevenless homolog
(SOS) , followed by activation of
transforming protein v-Ha-ras Harvey rat sarcoma viral oncogene homolog
(H-RAS), protein kinase V-raf-1 murine leukemia viral
oncogene homolog (c-Raf) and MAPK-cascade signaling.
Grb4 binding to p21 protein-activated kinase 1
(PAK1)  and to the WAS/WASL interacting
protein family, member 2 (WIRE) with subsequent activation
of Wiskott-Aldrich syndrome protein
(N-WASP) promotes complex of ARP
actin-related proteins homologs (Arp2/3) activation and
Actin polymerization . Activity of the
N-WASP is also facilitated by another
WASP interacting protein WAS/WASL interacting protein family
member 1 (WaspIP) .
Binding of Grb4 to LIM and senescent cell antigen-like
domains 1 (PINCH) and to Axin
regulates Beta-catenin activity and Wingless-type MMTV
integration site family (WNT) proteins signaling.
PINCH is a binding protein for Integrin-linked kinase
(ILK) , which phosphorylates downstream
glycogen synthase kinase 3 (GSK3) and down-regulates its
activity . PINCH-2, another member of the
PINCH protein family, forms a complex with
ILK and significantly inhibits the
PINCH/ILK interaction .
Axin forms a complex with Glycogen synthase kinase 3 beta
(GSK3 beta) and Beta-catenin
and promotes GSK3 beta-dependent phosphorylation of
Beta-catenin, thereby stimulating degradation of
Beta-catenin. GSK3 beta in turn
phosphorylates Axin in the complex, which is important for
the regulation of its stability .
GSK3 beta also phosphorylates neuronal
microtubule-associated protein Microtubule-associated protein tau
(Tau (MAPT)) .
This phosphorylation does not alter Tau's ability to bind to
Tubulin in microtubules but appears to be required for the
maintenance of the anterograde organelle transport in differentiated cells .
Paxillin is a focal adhesion-associated protein that also
could bind to both Tubulin alpha and
gamma of the cellular microtubule cytoskeleton .
Activation of Ephrin-B1 leads to phosphorylation
of focal adhesion kinase (FAK1)
by V-src sarcoma viral oncogene homolog (c-Src), which
increases FAK1 activity, and leads to redistribution of the
FAK1-binding protein Paxillin
and disassembly of focal adhesions .
These signaling pathways lead to rounding of cell morphology and cell repulsion.
A mechanism that may serve to turn off phosphorylation-dependent
Ephrin-B reverse signals involves delayed recruitment of the
FAP-1, which then dephosphorylates the cytoplasmic domain of
Ephrin-B ligands, even after dephosphorylating, can
initiate reverse signaling through binding to the Regulator of G-protein signaling 3
(RGS3), which catalyzes hydrolysis of GTP to GDP in the
Guanine nucleotide binding protein alpha inhibiting activity polypeptide 1
thereby inhibiting their activity. RGS3 might inhibit
Stromal cell derived factor 1 (SDF1)-mediated cerebellar
granule cell chemotaxis through Chemokine receptor 4 (CXCR4)
G-protein-coupled chemokine receptor . This
signaling mechanism may have broad implications for cell migratory behavior in different
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