The disappearance of fenestrae in Cas ΔSH3–expressing cells was associated with an attenuation check details of actin stress fiber formation, a marked reduction in tyrosine phosphorylation of Cas, and defective binding of Cas to CrkII. Conclusion: Cas plays pivotal roles in liver development through the reorganization of the actin cytoskeleton and formation of fenestrae in SECs. HEPATOLOGY 2010 The liver sinusoids are a unique multicellular system consisting of various cell types such as Kupffer

cells, stellate cells, and sinusoidal endothelial cells (SECs).1-3 These cells coordinately support and maintain hepatocyte survival, and their dysfunction results in hepatocyte apoptosis, which ultimately leads to liver failure.2, 4 SECs are not associated with basal laminas and possess characteristic cell-penetrating pores known as fenestrae.1, 3 Fenestrae provide a critical route for supplying oxygen and nutrients to hepatocytes and support the Dabrafenib nmr immunological contact of T cells with hepatocytes.5, 6 They are extremely sensitive to environmental conditions and change in number and diameter in response to external stimuli such as hormones, drugs, and toxins.1, 3 The molecular mechanisms regulating their structure are

not fully understood, but previous studies have shown that the actin cytoskeleton is deeply involved.1, 3, 7 p130Cas, Crk-associated substrate (Cas), the gene product of breast cancer anti-estrogen resistance 1, was initially identified as an approximately 130-kDa, highly tyrosine-phosphorylated protein in cells transformed by v-src and v-crk oncoproteins.8 It later became recognized as a central adaptor for actin cytoskeletal reorganization.9, 10 Under physiological conditions, Cas is phosphorylated on its tyrosines by stimuli that include integrin engagement, growth factor activation, 上海皓元医药股份有限公司 mechanical stretching, and bacterial infection.9, 10 Cas is composed of several different protein-protein interaction domains: N-terminal Src homology domain 3 (SH3), a substrate domain (SD) containing multiple

Tyr-x-x-Pro (YxxP) motifs, and a C-terminal Src-binding domain (SBD).8, 10 The SH3 domain binds to signaling molecules via their proline-rich domains, which include focal adhesion kinase,11 focal adhesion kinase–related nonkinase,12 proline-rich tyrosine kinase 2,13 protein tyrosine phosphatase 1B,14 protein tyrosine phosphatase–PEST (proline, glutamate, serine, and threonine7rpar;,15 guanine nucleotide exchange factor C3G,16 and zinc finger protein CIZ (Cas-interacting zinc finger protein).17 The multiple YxxP motifs in the SD serve as docking sites for the Src homology domain 2 (SH2) domains of the adaptor proteins CrkII18 and non catalytic region of tyrosine kinase adaptor protein (Nck)19 and for the SH2 domain containing inositol 5-phosphatase 2.