Disease relevance of MARK2

• In conclusion, flot-2 overexpression is associated with melanoma progression, with increased PAR-1 expression, and with transformation of SB2 melanoma cells to a highly metastatic line [1].
• Flot-2 binds to PAR-1, a known upstream mediator of major signal transduction pathways implicated in cell growth and metastasis, and may thereby influence tumor progression [1].
• These results support a role for proteinases and PARs in intestinal disease and provide new directions for possible therapeutic applications of PAR1 antagonists [2].
• OBJECTIVE: The purpose is to examine the responsiveness of the Health Utilities Index Mark 2 (HUI2), Mark 3 (HUI3), and other generic and disease-specific measures in osteoarthritis patients undergoing total hip arthroplasty (THA) [3].
• However, except in invasive lobular carcinoma (ILC) and inflammatory breast carcinoma (IBC), CE-CT showed the best correlation (R insertion mark2 = 0.537) [4].

Psychiatry related information on MARK2

• We suggest that although the four MARK/PAR-1 kinases might play multiple cellular roles in concert with different targets, MARK4 is likely to be directly involved in microtubule organization in neuronal cells and may contribute to the pathological phosphorylation of tau in Alzheimer's disease [5].
• Psychometric properties of the Health Utilities Index Mark 2 system in paediatric oncology patients [6].

High impact information on MARK2

• Treating cells with Wnt increases endogenous PAR-1 activity coincident with Dsh phosphorylation [7].
• The PAR-1 project resulted in a pharmacological tool compound that facilitated in vivo proof-of-principle studies, whereas the vasopressin and fibrinogen receptor projects resulted in several preclinical development compounds, three of which advanced into human clinical trials [8].
• Conversely, EMK1 overexpression induced the appearance of intercellular lumina and horizontal MT arrays in MDCK cells, making EMK1 the first known candidate to regulate the developmental branching decision between hepatic and columnar epithelial cells [9].
• Knocking down MARK2 expression with small interfering RNAs induced formation of multiple axon-like neurites and promoted axon outgrowth [10].
• Ectopic expression of MARK2 caused phosphorylation of tau (S262) and led to loss of axons, and this phenotype was rescued by expression of PAR-3, PAR-6, and aPKC [10].

Biological context of MARK2

• Our first finding that treatment of cells with LiCl, a selective inhibitor of another major tau kinase, glycogen synthase kinase-3beta (GSK-3beta), inhibits phosphorylation of Ser-262 of tau led us to investigate the possible involvement of GSK-3beta in MARK2 activation [11].
• SAXS (small-angle X-ray scattering) analysis of inactive and active LKB1-phosphorylated MARK2 revealed that activation of MARK2 is accompanied by a significant conformational change that alters the orientation of the UBA domain with respect to the catalytic domain [12].
• Up-regulation of PAR-1 was additionally confirmed in SB2-flot-2 cells and melanoma cell lines [1].
• Although MELK has been implicated in regulating the cell cycle, our data suggest that PIG-1, like other PAR-1 family members, regulates cell polarity [13].
• Human serine/threonine protein kinase EMK1: genomic structure and cDNA cloning of isoforms produced by alternative splicing [14].

Anatomical context of MARK2

• The Ser/Thr kinase MARK2 phosphorylates tau protein at sites that cause detachment from microtubules in Alzheimer neurofibrillary degeneration [15].
• On the other hand, one of the mammalian PAR-1 kinases, PAR-1b/EMK1/MARK2, localizes to the lateral membrane in a complimentary manner with aPKC, but little is known about its role in apicobasal polarity of epithelial cells as well as its functional relationship with aPKC [16].
• Protein kinase Emk1/Par1 (GenBank accession no. X97630) has been identified as a regulator of the immune system homeostasis [17].
• Although MARK2 transfected alone destabilizes microtubules and stabilizes actin stress fibers, PAK5 keeps microtubules stable through the down-regulation of MARK2 but destabilizes the F-actin network so that stress fibers and focal adhesions disappear and cells develop filopodia [18].
• These results, together with our recent demonstration that PAR-1 promotes morphological features of hepatocytes in MDCK cells, indicate that Par-1 modulates the developmental decision to build a columnar versus a hepatic epithelial cell [19].

Associations of MARK2 with chemical compounds

• These results indicate that phosphorylation of Rab11-FIP2 on serine 227 by MARK2 regulates an alternative pathway modulating the establishment of epithelial polarity [20].
• The formation of neurites in N2a cells is blocked if MARK2 is inactivated, either by transfecting a dominant negative mutant, or by MARK2 inhibitors such as hymenialdisine [21].
• Higher platelet reactivity associated with PAR-1 IVSn-14 A allele homozygotes persists despite clopidogrel therapy [22].
• Vapour concentrations from a halothane Cyprane (Fluotec) Mark 2 increased in relation to the density of carrier gas, whereas the concentrations delivered by an enflurane Ohio vaporizer decreased [23].
• Background: The role of the tyrosine kinase pp60(src) in PAR-1-dependent Ca(2+) entry was investigated in human platelets. pp60(src) plays a role in thapsigargin (TG)-evoked store-operated Ca(2+) entry (SOCE), which is thought to be a major component of thrombin-evoked Ca(2+) entry [24].

Regulatory relationships of MARK2

• PAK5 suppresses the activity of MARK2 toward its target, tau protein [18].

Other interactions of MARK2

• The adult statures of a sample of 71 Canadian boys from the Saskatchewan Longitudinal Growth Study were predicted using the original TW Mark 1 and the new TW Mark 2 prediction equations [25].
• We report the X-ray structure of the catalytic and ubiquitin-associated domains (UBA) of human MARK2 [15].
• Human EMK1 is located on 11q12-q13, close to COX8 and FTH1 [26].
• The results point to an inverse relationship between actin- and microtubule-related signaling by the PAK5 and MARK2 pathways that affect both cytoskeletal networks [18].
• We identify EMK and C-TAK1, two members of the microtubule affinity-regulating kinase (MARK)/Par-1 family, as regulators of this process [27].

Analytical, diagnostic and therapeutic context of MARK2

• By Northern blot, human EMK1 was shown to be encoded by a single mRNA ubiquitously expressed [14].
• Splicing alterations in human renal allografts: detection of a new splice variant of protein kinase Par1/Emk1 whose expression is associated with an increase of inflammation in protocol biopsies of transplanted patients [17].
• We examine the relationship between Visual Analogue Scale (VAS) and Standard Gamble (SG) assumed in the development of the multiplicative multi-attribute utility functions (M-MAUFs) for the Health Utilities Index (HUI) Mark 2 and Mark 3, using data from a UK valuation study of the HUI2 [28].
• A decrease of 0.1 units in HUI Mark 2 (HUI2) self-care single-attribute utility score was associated with an increased hazard of death of 30% (P = .023) for patients with low-grade tumors (n=25) [29].
• A portable Mark 2 aid was developed to enable clinical trials to be carried out on profoundly deaf people [30].

References