Antibodies to Adhesion Molecules and Related Proteins

Catenins
Catenins are mammalian cytoplasmic homologs of the armadillo protein family in Drosophila. The members are α-, β-, δ-, and γ- (plakoglobulin). β‑catenin is widely expressed in all tissues while δ‑catenin is brain specific. Catenins are characterized by a series of imperfect 42 amino acid repeats (Armadillo repeat domains, ARD) which are implicated in protein-protein interactions. Binding of protein partners through ARDs take place in overlapping and mutually exclusive fashion. Catenins are multi-functional proteins. β‑catenin, in particular, plays a central role in the β-Catenin Pathway and β‑catenin dysfunction has been implicated in carcinogenesis, metastasis, and neurodegeneration in Alzheimer′s disease.
Catenins are structural proteins and key component of cell-cell adhesion in molecular complex with E-Cadherins. In the cadherin adhesion complex (CAC), β‑catenin (or γ-) binds to E-Cadherin and α‑catenin, which in turns binds to vinculin and other actin-associated proteins and the actin cytoskeleton. The association of β‑catenin with the various molecular components of the CAC is regulated by a complex pattern of tyrosine phosphorylation. Disruption of the CAC is associated with increased tumor invasiveness.
Compelling evidence exists that β‑catenin is a key player in signal transduction in Wingless-Wnt and NOTCH cell-cell signaling pathways that are postulated to be mutually inhibitory. This signal transduction role is sometimes called the β-Catenin Pathway. In the absence of Wingless-Wnt signal free cytoplasmic β‑catenin is low. Wnt binding to its receptor leads to the stabilization of free β‑catenin, its binding to transcription factor TCF-LEF (T Cell Factor, transcription factor) and translocation to the nucleus resulting in induction of gene expression in proliferation or apoptosis. An important aspect of β‑catenin signaling involves its shuttling between the cytoplasmic membrane, where it is integrated into the tight junction, and nucleus where it acts as a transcription coactivator of TCF.
In an important body of recent work, β‑catenin is found as a component of the ~250 kDa complex with processed PS1 (presenilin 1, NTF, N‑terminal fragment & CTF, C‑terminal fragment) in the ER and the Golgi apparatus. β‑catenin is found to directly interact with PS1-CTF but not with PS1-NTF. In the absence of β‑catenin, PS1-CTF-NTF complex is non-functional. Mutations in PS1 caused increased degradation of β‑catenin in brain. Alternative caspase cleavage of PS-1 leads to loss of binding of β‑catenin.
The molecular organization of β‑catenin reflects its diverse function. It has N‑terminal phosphorylation sites for GSK-3 (glycogen synthase kinase, phosphorylation leads to degradation via the ubiquitin proteasome compartment). This is followed by a binding site for β‑catenin and overlapping ARD interactions sites for Axin/conductin (scaffold protein, facilities GSK-3 mediated phosphorylation), APC (Adenomatous Polyposis Coli, tumor suppressor in human colon cancer and a negative regulator of Wingless pathway) gene product, TCF and E-Cadherin. In addition there is a transactivation domain on the C‑terminal.

Vascular endothelial cell interactions and signaling
Endothelial cells use cell adhesion molecules, such as integrins and cadherins to attach themselves to each other and to the vascular extracellular matrix. Vascular endothelial (VE)-cadherin mediates the calcium-dependent interactions between neighboring endothelial cells. These adherens junctions are believed to provide a mechanical barrier to interendothelial leakage. The short cytoplasmic tail of VE-cadherin is able to interact with the plakoglobin complex (α-, β-, and γ-catenin) and this complex interacts with α-actinin and vinculin to link the VE-cadherin-catenin complex to the actin cytoskeleton. VE-cadherin coordinates with VEGFR-2 (Flk-1) to mediate PI₃K/Akt-dependent endothelial cell survival. Additionally, endothelial cells adhere to the extracellular matrix (ECM) through interactions with cell surface heterodimeric integrins (e.g., αVβ3). The ECM is a dense network of collagen and elastin contained in a complex of proteoglycans and glycoproteins. The engagement of integrins with the ECM causes the activation of focal adhesion molecules, such as focal adhesion kinase (FAK). Activated FAK recruits Src, which phosphorylates FAK on additional sites allowing for the subsequent recruitment of signaling molecules such as phosphatidylinositol 3-kinase (PI₃K), CAS, and paxillin to focal adhesions. In addition to adhesion-dependent cell survival, endothelial cells can also respond to receptor tyrosine kinase-mediated survival signals via VEGF through its receptor VEGFR-2 and via angiopoietin-1 (ANG-1) through its receptor Tie2. Both VEGF and ANG-1 allow endothelial cells to escape apoptosis (anoikis) upon detachment from the ECM.