Biology subjects

Simpkins, C.

Publications and source records attributed to Simpkins, C..

3 recordsLinked to original sources

bioRxiv2022

Focal adhesion assembly requires phosphorylation signaling

Integrin-mediated cell attachment rapidly induces tyrosine kinase signaling. Despite years of research, the role of this signaling in integrin activation and focal adhesion assembly is unclear. We provide evidence that the Src-family kinase (SFK) substrate Cas (Crk-associated substrate, p130Cas, BCAR1) is phosphorylated, and associated with its effectors, Crk/CrkL, in clusters that are precursors of focal adhesions. The initial phospho-Cas clusters contain integrin {beta}1 in its inactive, bent closed, conformation. Later, phospho-Cas and total Cas levels decrease as integrin {beta}1 is activated and core focal adhesion proteins including vinculin, talin, kindlin and paxillin are recruited. Cas is required for cell spreading and focal adhesion assembly in epithelial and fibroblast cells on collagen and fibronectin. Cas cluster formation requires Cas, Crk/CrkL, SFKs and Rac1 but not vinculin. Rac1 provides positive feedback onto Cas through reactive oxygen, opposed by negative feedback from the ubiquitin proteasome system. The results suggest a two-step model for focal adhesion assembly in which clusters of phospho-Cas, effectors and inactive integrin {beta}1 grow through positive feedback prior to integrin activation and recruitment of core focal adhesion proteins.

cell biology↗

bioRxiv2022

Existing caribou habitat and demographic models are poorly suited for Ring of Fire impact assessment: A roadmap for improving the usefulness, transparency, and availability of models for conservation

Decision making in conservation science often relies on the best available information. This may include using models that were not designed for purpose and are not accompanied by an assessment of limitations. To begin addressing these issues, we sought to reproduce, and evaluate the suitability of, the best available models for predicting impacts of proposed mining on boreal woodland caribou (Rangifer tarandus caribou) resource selection and demography in northern Ontario. We then evaluated their suitability for projecting the impacts of development in the Ring of Fire region. To aid in accessibility, we developed an R package for data preparation, analyses of resource selection, and demographic parameters. We found existing models were either ill suited, or lacking, for ongoing regional planning. The specificity of the regional resource selection model limited its usefulness for predicting impacts of development, and the high variability across caribou ranges limited the usefulness of a national aspatial demographic model for predicting range-specific impacts. Variability in model coefficients across caribou ranges suggests selection responses vary with habitat availability (i.e. a functional response) while demographic responses continue to decline with increasing disturbance. Models designed for forecasting that are continuously updated by range-specific demographic and habitat information, are required to better inform conservation decisions and ongoing policy and planning practices in the Ring of Fire region.

ecology↗

bioRxiv2021

A Cas-BCAR3 co-regulatory circuit controls lamellipodia dynamics

Integrin adhesion complexes regulate cytoskeletal dynamics during cell migration. Adhesion activates phosphorylation of integrin-associated signaling proteins, including Cas (p130Cas, BCAR1), by Src-family kinases. Cas regulates leading-edge protrusion and migration in cooperation with its binding partner, BCAR3. However, it has been unclear how Cas and BCAR3 cooperate. Here, using normal epithelial cells, we find that BCAR3 localization to integrin adhesions requires Cas. In return, Cas phosphorylation, as well as lamellipodia dynamics and cell migration, requires BCAR3. These functions require the BCAR3 SH2 domain and a specific phosphorylation site, Tyr 117, that is also required for BCAR3 downregulation by the ubiquitin-proteasome system. These findings place BCAR3 in a co-regulatory positive-feedback circuit with Cas, with BCAR3 requiring Cas for localization and Cas requiring BCAR3 for activation and downstream signaling. The use of a single phosphorylation site in BCAR3 for activation and degradation ensures reliable negative feedback by the ubiquitin-proteasome system.

cell biology↗