Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 625

Table 10.12. Effectors of netrin-1 signaling (Source: [ 1215 ]).

GTPases CDC42, Rac, Rho

Kinases FAK, MAPK, PAK, PI3K, PKA, PKG, PLC γ ,Src

Transcription factors ELk1, NFAT, P53

Raf and MAPK module. Adaptor SHC also activates phosphatidylinositol 3-kinase
and protein kinase-B.
Netrins activate small GTPases Rac, Rho, and CDC42 (Table 10.12 ). Netrin-1
bound to DCC recruits extracellular signal-regulated kinases ERK1 and ERK2 to a
DCC receptor complex. Receptor DCC also interacts with focal adhesion kinases
and Src kinases.
Netrin-1 acts a survival cue. Once bound to DCC and Unc5h, it activates caspase-
3 that cleaves the death domains of these receptors, the latter activating apoptotic
caspase-9. Moreover, Unc5b targeted by P53 mediates P53-dependent apoptosis
until it binds netrin-1.

10.6.1.3 Ephrins

Ephrin-A1 mediates TNF -induced angiogenesis in vivo [ 1216 ]. Ephrin-B2 and

its receptor EPHb are arterial markers. Receptor EPHb activates Src kinase via
a cleavage of ephrin-B2, releasing a cytoplasmic C-terminal fragment ( C 1 ephrin-
B2) that is further processed by the presenilin-1-

α

-secretase complex to produce
intracellular C 2 ephrin-B2 peptide. 32 Peptide C 2 ephrin-B2 binds Src kinase, thereby
impeding Src association with CSK kinase, a Src inhibitor, and allowing Src
autophosphorylation [ 1217 ]. 33

γ

Activated Src phosphorylates ephrin-B2, inhibiting

its processing by -secretase and triggering the recruitment of GRB4 to ephrin-B2.

Adaptor GRB4 controls actin dynamics and cell migration, thereby sprouting of
endothelial cells.
Endothelial cells express guidance molecules for angiogenesis, such as EPHb4
and its ligand ephrin-B2 [ 1218 ]. EPHb4 is a negative regulator of blood vessel
branching, leading to circumferential vessel growth rather than angiogenic sprouting
and vessel interconnection. EPHb4 and ephrin-B2 restrict migration of endothelial
cells. Moreover, EPHb4 reduces vascular permeability via angiopoietin-1-TIE2
activation at the endothelium-pericyte interface. EPHb4 reverse signaling via
ephrin-B2 represents the predominant signaling pathway, being independent of
EPHb4 RTK activity and EPHb4 forward signaling.

γ

32 Presenilin-1 is a widespread transmembrane protein. It is cleaved into N-terminal ( N PS1) and C-
terminal ( C PS1) fragments that associate to form a functional heterodimer. It promotes

γ -secretase

processing of substrates.
33 C-terminal Src kinase (CSK) binds Src kinase and prevents its activation by precluding its
autophosphorylation (Tyr418).