CAS proteins in normal and pathological cell growth control

Abstract

Proteins of the CAS (Crk-Associated Substrate) family (BCAR1/p130Cas, NEDD9/HEF1/Cas-L, EFS/SIN and CASS4/HEPL) are integral players in normal and pathological cell biology. CAS proteins act as scaffolds to regulate protein complexes controlling migration and chemotaxis, apoptosis, cell cycle, and differentiation, and have more recently been linked to a role in progenitor cell function. Reflecting these complex functions, over-expression of CAS proteins has now been strongly linked to poor prognosis and increased metastasis in cancer, as well as resistance to firstline chemotherapeutics in multiple tumor types including breast and lung cancers, glioblastoma, and melanoma. Further, CAS proteins have also been linked to additional pathological conditions including inflammatory disorders, Alzheimer's and Parkinson's disease, as well as developmental defects. This review will explore the roles of the CAS proteins in normal and pathological states in the context of the many mechanistic insights into CAS protein function that have emerged in the past decade.

Nedd9 restrains renal cystogenesis in Pkd1 −/− mice

“…Although Nedd9 has been much studied in the context of cancer (35), little is known about the role of this protein in other pathological conditions. Our data demonstrate that loss of Nedd9 strongly enhances the kidney expansion and cystogenesis induced by the loss of Pkd1 either before or after the P13 developmental switch (23), for the first time, to our knowledge, defining Nedd9 as a candidate modifier gene for human ADPKD.…”

Integrin signalling adaptors: not only figurants in the cancer story

“…The CAS family comprises four members: p130CAS (also known as breast cancer anti-oestrogen resistance 1 (BCAR1)), NEDD9 (also known as HEF1 or CAS-L), embryonal Fynassociated substrate (EFS, also known as SIN) and CAS scaffolding protein family member 4 (CASS4, also known as HEPL). They are characterized by the presence of multiple conserved sequence motifs, such as SH3 and proline-rich domains and extensive post-translational modifications, mainly consisting of tyrosine and serine phosphorylation 3,4 (Figure 1). CAS proteins differ in patterns of expression, for esample in normal tissues, whilst p130CAS is ubiquitously expressed, NEDD9 expression is confined to the lungs and kidneys 3,4 .…”

“…They are characterized by the presence of multiple conserved sequence motifs, such as SH3 and proline-rich domains and extensive post-translational modifications, mainly consisting of tyrosine and serine phosphorylation 3,4 (Figure 1). CAS proteins differ in patterns of expression, for esample in normal tissues, whilst p130CAS is ubiquitously expressed, NEDD9 expression is confined to the lungs and kidneys 3,4 . CASS4 7 and EFS 8 are less abundant and specifically expressed in spleen and lung (CASS4) and T-lymphocytes, thymus, brain and skeletal tissue (EFS), making their functions limited to specific context.…”

“…Current knowledge implies that in cancer cells integrins, receptor tyrosine kinases (RTKs) and cytokine receptors constitute joint modules in which attachment to the ECM confers positional control to the activated signalling pathways allowing cells to respond to soluble growth factors, which thereby determine the nature and the extent of the response 1,2 . This control mainly resides on the recruitment of adaptor proteins that behave as molecular hubs for intracellular signalling and organise complex signalling networks in time and space [3][4][5][6] . The biological effects regulated by integrin and RTK signalling adaptors are dependent on their expression levels and on their phosphorylation status, which determines the association with binding effectors.…”

Src Points the Way to Biomarkers and Chemotherapeutic Targets

“…Other kinases and signaling molecules interact with the C-terminal domain of Cas and related proteins. 43,44 Numerous studies have focused on the biological roles of Cas in normal cell physiology, as well as the importance of Cas in Src-mediated cellular transformation (reviewed more extensively in Bouton et al, 43 Tikhmyanova et al, 44 Chodniewicz and Klemke, 53 and Defilippi et al 54 ). Cas undergoes rapid phosphorylation following mitogenic stimulation and in response to fibronectin attachment via integrin receptors.…”