Identification of novel regulatory mechanisms for for Cdc42 GTPase-activating protein CdGAP/ARHGAP31, a protein involved in development and cancer
Bibliographic record
Abstract
Abstract The small Rho GTPase proteins act as molecular switches that regulate diverse cellular processes linked mostly to the actin-cytoskeleton remodeling making them essential regulators of cell adhesion, migration and invasion. Dysregulation of their activities can result in different abnormal phenotypes particularly, tumor progression and metastasis. Hence, regulators of Rho GTPases such as Rho guanine nucleotide exchange factors (RhoGEFs) and Rho GTPase-activating proteins (RhoGAPs), are critical for normal cellular responses and are targets for subversion during oncogenic transformation. CdGAP (Cdc42 GTPase-activating protein) is a member of a well-conserved subfamily of RhoGAP proteins and a negative regulator of the small Rho GTPases, Rac1 and Cdc42. Associated with a rare developmental disorder (AOS, Adams-Oliver Syndrome) and required for a normal angiogenesis, CdGAP plays important roles in the regulation of cell migration and proliferation during early development. In addition, recent findings characterize CdGAP as an essential synergistic component between TGFβ and HER2/Neu/ErbB-2 signaling pathways which play a positive role in cancer, particularly breast cancer. CdGAP is regulated by lipid binding, protein-protein interactions and phosphorylation, still these mechanisms are not well understood. In this work we first investigate the interaction between CdGAP and its negative regulator, the endocytic protein Intersectin. Using an in vitro approach, we identify a novel, atypical xKx(K/R) (SKSKK) motif in the basic rich (BR) region of CdGAP that directly interacts with the Intersectin-SH3D domain. Moreover, the well-conserved motif is required for the regulation of CdGAP activity following Intersectin binding. Next, we investigate CdGAP phosphorylation and identify two regulatory phospho-serines in the C-terminal (CT) tail, Ser-1093 and Ser-1163, that are phosphorylated by the AGC-kinase family member, RSK1. Finally, we show that 14-3-3 family members bind and regulate both the cellular localization and activity of CdGAP in a Ser-1093 and Ser-1163 phosphorylation-dependent manner. Overall, this work provides two novel CdGAP-regulatory mechanisms that can be applied in therapeutic approaches targeting this RhoGAP, particularly in breast cancers.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".