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Pili and Hosts
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
Furthermore, a new system of nomenclature was proposed, in which P. aeruginosa type IV pili, or TFP, were divided into five distinct phylogenetic groups, classifying the above-described PAO, PAK, and some other pilins to group II (Kus et al. 2004). Group II was formed by pilins which were the smallest among the five groups and the only ones lacking associated accessory proteins, making them an exception in the P. aeruginosa pilin repertoire (Kus et al. 2004).
Gastrointestinal Tract
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Judit E. Markovits, Graham R. Betton, Donald N. McMartin, Theresa Boulineau
New promising biomarkers of GI toxicity were identified in rats treated with a PAK-4 inhibitor. Preliminary findings indicated the utility of plasma citrulline and fecal miRNA194, at least in the model used (John-Baptiste et al. 2012). In follow-up studies, using PAK4 inhibitors as well as a heat shock protein 90 inhibitor and an NSAID, miRNA194 and miR-215 appeared to be quantitative, noninvasive, and sensitive biomarkers for drug-induced intestinal toxicity (Kalabat et al. 2017).
Pigmented nonmelanocytic skin lesions
Published in Dimitris Rigopoulos, Alexander C. Katoulis, Hyperpigmentation, 2017
Elvira Moscarella, Simonetta Piana, Caterina Longo, Giuseppe Argenziano
They typically present as pink to red macules, with a variably scaly surface. Less frequently, AKs may present a clinically visible pigmentation, pigmented AK (PAK). PAK can be difficult to differentiate from other pigmented lesions, such as melanoma and lentigo maligna melanoma, SL, early SK, and LPLK. In the context of actinically damaged skin, characterized by the presence of mottled pigmentation, discriminating between benign macules and pigmented tumors may be challenging; thus, histopathologic confirmation is frequently required in the diagnosis of PAK in order to exclude melanoma.
Combination of PAKs inhibitors IPA-3 and PF-3758309 effectively suppresses colon carcinoma cell growth by perturbing DNA damage response
Published in International Journal of Radiation Biology, 2023
Muzaffer Dukel, Kayahan Fiskin
P21‐activated kinases (PAKs) are serine/threonine kinases that have the capability to promote oncogenic signaling pathways including directional motility, invasion, metastasis, cell cycle progression, and angiogenesis (Ye and Field 2012; Radu et al. 2014). The upregulation of PAKs in tumors is referred to as leading to resistance to anticancer drug-induced cell death in tumors (Marlin et al. 2009; Lu et al. 2017). Moreover, the overactivation of PAKs causes anti-apoptotic actions that prolong cell survival (Molli et al. 2009). Besides, PAKs have several vital roles during numerous cellular processes that can be distinguished during cancer development. PAK4 and PAK5 mutations are linked to colon and lung cancers, while PAK1 is overexpressed in both gene and protein levels or hyperactivated in colon cancer (Dummler et al. 2009). On the other hand, an early study indicated that PAK4 is required for anchorage-independent cell growth and it is overexpressed in colon cancer cells (Callow et al. 2002). In addition, changes to PAK1 mRNA, protein, and activity have been reported in a variety of human malignancies, including breast (Li et al. 2008), glioblastoma (Aoki et al. 2007), liver (Ching et al. 2007), kidney (O’Sullivan et al. 2007), prostate (Goc et al. 2013), and pancreas (Yeo et al. 2017). Moreover, PAK1 and PAK4 have been reported to be involved in a large number of oncogenic properties, including anti-apoptosis and metastasis, and, not surprisingly, this kinase is recognized as a potential target for the treatment of human cancers such as colon cancer (Carter et al. 2004; Liu et al. 2008).
Drug discovery targeting p21-activated kinase 4 (PAK4): a patent review
Published in Expert Opinion on Therapeutic Patents, 2021
Hanxun Wang, Peilu Song, Yinli Gao, Lanlan Shen, Hanqin Xu, Jian Wang, Maosheng Cheng
Type II PAK members (PAK4, 5 and 6) share a high sequence identity, which makes it a formidable task to differentiate the selectivity toward type II PAK4 isoforms. As disclosed from the structural superimposition of type II PAK members (Figure 3), they own highly similar conserved amino acids, such as Cys462PAK4/Cys590PAK5/Cys548PAK6 at the same position. In addition, diverse conformations for similar amino acids are also observed. For example, the side chains of Arg359PAK4/ARG487PAK5/ARG445PAK6 locate at different position, and Asn365PAK4/Asn493PAK5/ Asn451PAK6 are flexible. Moreover, their P-loop regions are not overlapped. Thereby, we hypothesize such difference could be employed to design isoform selective PAK4 inhibitors.
S1P in the development of atherosclerosis: roles of hemodynamic wall shear stress and endothelial permeability
Published in Tissue Barriers, 2021
Christina M Warboys, Peter D Weinberg
Exposure of endothelial cells to S1P results in rapid actin polymerization and dynamic reorganization of the actin cytoskeleton, forming a prominent cortical actin band29,33,36,37,41 that is essential for the barrier-enhancing effects of S1P.29 Several studies have also shown that Rac GTPase is rapidly activated in response to S1P29,38,39,41 and that this depends on the activation of PI3K and recruitment of Tiam1, a Rac1 guanine nucleotide exchange factor.37 Rac plays a critical role in mediating S1P-induced cytoskeletal remodeling via activation of p21-associated Ser/Thr kinase (PAK).29,41 PAK may act at several levels to promote the dynamic reorganization of the cytoskeleton into dense peripheral bands that strengthen barrier function. Myosin light chain (MLC) can be phosphorylated by PAK61 and indeed phosphorylated MLC has been shown to localize to peripheral bands in response to S1P.29,36 PAK also phosphorylates and activates LIM kinase (LIMK), which inhibits cofilin (an actin severing protein) thus preventing actin depolymerization and promoting the formation of actin filaments.62