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PAK2
PAK2 Full Name
p21 protein (Cdc42/Rac)-activated kinase 2
PAK2 Introduction
PAK2 is a member of the family of p21-activated kinases (PAK), of the Group I PAKs (group I PAKs: PAK1, PAK2, PAK3) that are activated by binding to small GTPases Cdc42 and Rac. It has an N-terminal autoinhibitory domain and a C-terminal kinase domain. In its unstimulated state, the autoinhibitory domain binds to and tethers the kinase domain, holding PAK2 in an inactive, folded conformation. Upon stimulation by an upstream signal, the GTP-bound active form of Cdc42 or Rac binds to the p21-binding domain (PBD) of PAK2, releases it from autoinhibition, and results in autophosphorylation and full activation of PAK2. This is the canonical activation mechanism of PAK2. In addition to the canonical GTPase-dependent mechanism, PAK2 is also uniquely activated via a GTPase-independent mechanism by proteolytic cleavage by effector proteases, such as caspase-3, at a unique site in the PBD during apoptosis, resulting in a constitutively active C-terminal kinase fragment with a nonredundant function from the full-length PAK2. This is the molecular basis for the dual role of PAK2 in cell fate determination.
Figure 1. Structure and activation of PAK2. (Source: Wu M, et al. 2024)
The central paradoxical role of PAK2 in life of a cell could be classified into three dimensions: survival vs. apoptosis, cytoskeletal remodeling, and metabolism. In a normal condition, the full-length of PAK2 usually has a role in the promotion of cell survival. For example, activated PAK2 phosphorylates the pro-apoptotic protein Bad and sequesters it from binding to Bcl-2/Bcl-xL, which suppresses apoptosis. PAK2 is also essential for mechanotransduction. PAK2 can be recruited to E-cadherin-based cell-cell junctions to orchestrate the remodeling and reinforcement of the actin cytoskeleton, thereby allowing cells to survive from mechanical force induced damages and apoptosis from outside forces. In this case, PAK2 and AMP-activated protein kinase (AMPK) work together to not only reinforce the structure of the cell, but also to promote glucose intake and ATP production, which supplies energy for cells that are under stress or high-load conditions. Some proteins like AMPK and Huntingtin can directly bind to PAK2 to prevent its cleavage by caspase and keep cells alive. In contrast, during the process of committing to cell death through apoptosis, caspase-cleaved PAK2 will produce the pro-apoptotic PAK-2p34 fragment. The PAK-2p34 can then move into the nucleus and phosphorylate its substrates to further promote cell apoptosis.
In pancreatic cancer, the expression of PAK2 is upregulated and significantly correlated with a poor prognosis, rapid tumor progression, and distant metastasis (especially liver metastasis). Mechanistically, PAK2 promotes the malignancy and drug resistance of pancreatic cancer through various pathways, such as the systemic activation of TGF-β signaling, induction of angiogenesis, induction of epithelial-mesenchymal transition (EMT), and changes in energy metabolism. In breast cancer, PAK2 is also highly expressed. It inhibits chemotherapy-induced apoptosis by phosphorylating and inactivating downstream caspase-7, which may be a target to help overcome drug resistance.
Alternate Names for PAK2
PAK2; p21 protein (Cdc42/Rac)-activated kinase 2; PAK65; PAKgamma; serine/threonine-protein kinase PAK 2; p58; PAK-2; gamma-PAK; S6/H4 kinase; p21-activated kinase 2; p21 (CDKN1A)-activated kinase 2;
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