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Cas proteins: dodgy scaffolding in breast cancer.

Tornillo G, Defilippi P, Cabodi S - Breast Cancer Res. (2014)

Bottom Line: The members of the Cas protein family (p130Cas/BCAR1, Nedd9/HEF1, EFS and CASS4) are scaffold proteins required for the assembly of signal transduction complexes in response to several stimuli, such as growth factors, hormones and extracellular matrix components.Given their ability to integrate and coordinate multiple signalling events, Cas proteins have emerged as crucial players in the control of mammary cell proliferation, survival and differentiation.More importantly, it has been found that alterations of their expression levels result in aberrant signalling cascades, which promote initiation and progression of breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy; European Cancer Stem Cell Research Institute and Cardiff School of Biosciences, Cardiff University, Cardiff CF24 4HQ, UK.

ABSTRACT
The members of the Cas protein family (p130Cas/BCAR1, Nedd9/HEF1, EFS and CASS4) are scaffold proteins required for the assembly of signal transduction complexes in response to several stimuli, such as growth factors, hormones and extracellular matrix components. Given their ability to integrate and coordinate multiple signalling events, Cas proteins have emerged as crucial players in the control of mammary cell proliferation, survival and differentiation. More importantly, it has been found that alterations of their expression levels result in aberrant signalling cascades, which promote initiation and progression of breast cancer. Based on the increasing data from in vitro, mouse model and clinical studies, in this review we will focus on two Cas proteins, p130Cas/BCAR1 and Nedd9, and their coupled signalling pathways, to examine their role in mammary cell transformation and in the acquirement of invasiveness and drug resistance of breast cancer cells.

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Related in: MedlinePlus

p130Cas/BCAR1 and Nedd9 structural features and main interacting proteins. Schematic representation of Cas protein main domains: an amino-terminal SH3 domain followed by a proline-rich region (PRR), a substrate domain (SD), a serine rich region (SRR), and a carboxy-terminal domain (CT). The main proteins whose interaction has been demonstrated for both p130Cas and Nedd9 are indicated in black, the interactors specific for p130Cas are in red and those specific for Nedd9 are in green. Noteworthy, p125FAK binds to the SH3 domain while the Src family kinases bind to the CT domain. The substrate domain with the multiple YxxP motifs represents the site where Src family kinases extensively phosphorylate Cas proteins.
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Fig1: p130Cas/BCAR1 and Nedd9 structural features and main interacting proteins. Schematic representation of Cas protein main domains: an amino-terminal SH3 domain followed by a proline-rich region (PRR), a substrate domain (SD), a serine rich region (SRR), and a carboxy-terminal domain (CT). The main proteins whose interaction has been demonstrated for both p130Cas and Nedd9 are indicated in black, the interactors specific for p130Cas are in red and those specific for Nedd9 are in green. Noteworthy, p125FAK binds to the SH3 domain while the Src family kinases bind to the CT domain. The substrate domain with the multiple YxxP motifs represents the site where Src family kinases extensively phosphorylate Cas proteins.

Mentions: The Cas family comprises four members: p130Cas/BCAR1 (p130 Crk-associated substrate; also known as Breast cancer anti-estrogen resistance 1 (BCAR1)), Nedd9 (Neural precursor cell expressed, developmentally down-regulated 9; also called Human enhancer of filamentation 1 (HEF-1) or Cas-L), EFS (Embryonal Fyn-associated substrate) and CASS4 (Cas scaffolding protein family member 4). These proteins have a similar structure, which is characterized by the presence of multiple protein interaction domains and several tyrosine and serine phosphorylation motifs [2] (Figure 1).Figure 1


Cas proteins: dodgy scaffolding in breast cancer.

Tornillo G, Defilippi P, Cabodi S - Breast Cancer Res. (2014)

p130Cas/BCAR1 and Nedd9 structural features and main interacting proteins. Schematic representation of Cas protein main domains: an amino-terminal SH3 domain followed by a proline-rich region (PRR), a substrate domain (SD), a serine rich region (SRR), and a carboxy-terminal domain (CT). The main proteins whose interaction has been demonstrated for both p130Cas and Nedd9 are indicated in black, the interactors specific for p130Cas are in red and those specific for Nedd9 are in green. Noteworthy, p125FAK binds to the SH3 domain while the Src family kinases bind to the CT domain. The substrate domain with the multiple YxxP motifs represents the site where Src family kinases extensively phosphorylate Cas proteins.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4384296&req=5

Fig1: p130Cas/BCAR1 and Nedd9 structural features and main interacting proteins. Schematic representation of Cas protein main domains: an amino-terminal SH3 domain followed by a proline-rich region (PRR), a substrate domain (SD), a serine rich region (SRR), and a carboxy-terminal domain (CT). The main proteins whose interaction has been demonstrated for both p130Cas and Nedd9 are indicated in black, the interactors specific for p130Cas are in red and those specific for Nedd9 are in green. Noteworthy, p125FAK binds to the SH3 domain while the Src family kinases bind to the CT domain. The substrate domain with the multiple YxxP motifs represents the site where Src family kinases extensively phosphorylate Cas proteins.
Mentions: The Cas family comprises four members: p130Cas/BCAR1 (p130 Crk-associated substrate; also known as Breast cancer anti-estrogen resistance 1 (BCAR1)), Nedd9 (Neural precursor cell expressed, developmentally down-regulated 9; also called Human enhancer of filamentation 1 (HEF-1) or Cas-L), EFS (Embryonal Fyn-associated substrate) and CASS4 (Cas scaffolding protein family member 4). These proteins have a similar structure, which is characterized by the presence of multiple protein interaction domains and several tyrosine and serine phosphorylation motifs [2] (Figure 1).Figure 1

Bottom Line: The members of the Cas protein family (p130Cas/BCAR1, Nedd9/HEF1, EFS and CASS4) are scaffold proteins required for the assembly of signal transduction complexes in response to several stimuli, such as growth factors, hormones and extracellular matrix components.Given their ability to integrate and coordinate multiple signalling events, Cas proteins have emerged as crucial players in the control of mammary cell proliferation, survival and differentiation.More importantly, it has been found that alterations of their expression levels result in aberrant signalling cascades, which promote initiation and progression of breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy; European Cancer Stem Cell Research Institute and Cardiff School of Biosciences, Cardiff University, Cardiff CF24 4HQ, UK.

ABSTRACT
The members of the Cas protein family (p130Cas/BCAR1, Nedd9/HEF1, EFS and CASS4) are scaffold proteins required for the assembly of signal transduction complexes in response to several stimuli, such as growth factors, hormones and extracellular matrix components. Given their ability to integrate and coordinate multiple signalling events, Cas proteins have emerged as crucial players in the control of mammary cell proliferation, survival and differentiation. More importantly, it has been found that alterations of their expression levels result in aberrant signalling cascades, which promote initiation and progression of breast cancer. Based on the increasing data from in vitro, mouse model and clinical studies, in this review we will focus on two Cas proteins, p130Cas/BCAR1 and Nedd9, and their coupled signalling pathways, to examine their role in mammary cell transformation and in the acquirement of invasiveness and drug resistance of breast cancer cells.

Show MeSH
Related in: MedlinePlus