Cell adhesion receptors, tyrosine kinases and actin modulators: a complex three-way circuitry

300

290

In several pathological conditions, epithelial cells demonstrate a breakdown of barrier function and acquire an invasive phenotype. Endothelial cells in particular are maintained in a mesenchymal state during the cell invasion phase of angiogenesis. We show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120-and ␤-catenin, respectively, to the cytoplasmic tail of VE-cadherin. In fact, phosphorylation at either site led to the inhibition of cell barrier function. Cells expressing wild-type VE-cadherin showed decreased cell migration compared with cells lacking VE-cadherin, whereas expression of VE-cadherin with a simple phosphomimetic tyrosine-to-glutamic acid mutation of Y658E or Y731E was sufficient to restore the migratory response. These findings demonstrate that a single phosphorylation event within the VE-cadherin cytoplasmic tail is sufficient to maintain cells in a mesenchymal state.

Section: Discussionmentioning

confidence: 99%

Tyrosine Phosphorylation of VE-cadherin Prevents Binding of p120- and β-Catenin and Maintains the Cellular Mesenchymal State

Potter

Barbero²,

Cheresh

2005

300

290

“…In addition, co-expression of Fyn had no effect on the CAP4-flotillin interaction and vice versa, suggesting biochemically that these three proteins may be able to co-exist in the same complex. Fyn and other Src family kinases are well known regulators of integrin signaling and the actin cytoskeleton (39). Additionally, the role of Src kinases in insulin receptor signal transduction is well documented (37,40,41).…”

Section: Figmentioning

confidence: 99%

The Stomatin/Prohibitin/Flotillin/HflK/C Domain of Flotillin-1 Contains Distinct Sequences That Direct Plasma Membrane Localization and Protein Interactions in 3T3-L1 Adipocytes

DeYoung

Zhang

et al. 2005

121

122

Flotillin-1 is a lipid raft-associated protein that has been implicated in various cellular processes. We examined the subcellular distribution of flotillin-1 in different cell types and found that localization is cell type-specific. Flotillin-1 relocates from a cytoplasmic compartment to the plasma membrane upon the differentiation of 3T3-L1 adipocytes. To delineate the structural determinants necessary for its localization, we generated a series of truncation mutants of flotillin-1. Wild type flotillin-1 has two putative hydrophobic domains and is localized to lipid raft microdomains at the plasma membrane. Flotillin-1 fragments lacking the Nterminal hydrophobic stretch are excluded from the lipid raft compartments but remain at the plasma membrane. On the other hand, mutants with the second hydrophobic region deleted fail to traffic to the plasma membrane but are instead found in intracellular granule-like structures. Flotillin-1 specifically interacts with the adaptor protein CAP, the Src family kinase Fyn, and cortical F-actin in lipid raft microdomains in adipocytes. Furthermore, CAP and Fyn associate with different regions in the N-terminal sequences of flotillin-1. These results furthered our understanding for how flotillin-1 can function as a molecular link between lipid rafts of the plasma membrane and a multimeric signaling complex at the actin cytoskeleton.

“…Literature data have indicated that Src kinases can act in concert with Syk kinase to participate in membrane receptor complexes, which among others contain RTKs (38). SmVKR1 of S. mansoni is an RTK and was shown to be expressed in the ovary of females (23), thus co-localizing with SmTK6 and SmTK4 (13,17).…”

Section: Journal Of Biological Chemistry 42329mentioning

confidence: 99%

Characterization of the Src/Abl Hybrid Kinase SmTK6 of Schistosoma mansoni

Beckmann

Hahnel

Cailliau

et al. 2011

Background: SmTK6 was identified as interaction partner of SmTK4. Results: SmTK6 is a Src/Abl hybrid kinase and interacts also with the uncommon SmVKR1 and SmTK3. Conclusion: SmTK6 is suggested to be part of a complex of receptors, Syk and Src kinases, which are involved in gonad development. Significance: SmTK6 represents an Abl kinase progenitor, for which a function in reproduction could be assigned.