Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP-activated protein kinase (AMPK). A total of 12 human kinases (NUAK1, NUAK2, BRSK1, BRSK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4 and MELK) are related to AMPK. Here we demonstrate that LKB1 can phosphorylate the T-loop of all the members of this subfamily, apart from MELK, increasing their activity >50-fold. LKB1 catalytic activity and the presence of MO25 and STRAD are required for activation. Mutation of the T-loop Thr phosphorylated by LKB1 to Ala prevented activation, while mutation to glutamate produced active forms of many of the AMPK-related kinases. Activities of endogenous NUAK2, QIK, QSK, SIK, MARK1, MARK2/3 and MARK4 were markedly reduced in LKB1-deficient cells. Neither LKB1 activity nor that of AMPK-related kinases was stimulated by phenformin or AICAR, which activate AMPK. Our results show that LKB1 functions as a master upstream protein kinase, regulating AMPK-related kinases as well as AMPK. Between them, these kinases may mediate the physiological effects of LKB1, including its tumour suppressor function.
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PMID:LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. 1497 52

Genes most closely related to adenosine monophosphate (AMP)-activated protein kinase, including SAD kinases and Par-1 regulate cell polarity, although AMP-activated protein kinase (AMPK) modulates cellular energy status. LKB1 (Par-4) is required for normal activation of AMPK in the liver and also regulates cell polarity. AMPK is proposed to inhibit energy consuming activity while initiating energy producing activity during energy limitation. Demonstration that metformin, a common drug for Type 2 diabetes, requires LKB1 for full therapeutic benefit has increased interest in AMPK signaling. Despite the potential importance of AMPK signaling for diabetes, metabolic syndrome and even cancer, the developmental processes regulated by AMPK in genetically mutant animals require further elucidation. Mouse conditional null mutants for AMPK activity will allow genetic elucidation of AMPK function in vivo. This perspective focuses on sequence and structural moieties of AMPK and genetic analysis of AMPK mutations. Interestingly, the predicted protein structure of the carboxy-terminus of AMPKalpha resembles the carboxy-terminal KA-1 domain of MARK3, a Par-1 orthologue.
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PMID:Opinion: alternative views of AMP-activated protein kinase. 1765 78

AMP-activated protein kinase (AMPK) is a key regulator of cellular and whole-body energy homeostasis. Recently, 12 AMPK-related kinases (BRSK1, BRSK2, NUAK1, NUAK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4 and MELK) were identified that are closely related by sequence homology to the catalytic domain of AMPK. The protein kinase LKB1 acts as a master upstream kinase activating AMPK and 11 of the AMPK-related kinases by phosphorylation of a conserved threonine residue in their T-loop region. Further sequence analyses have identified the eight-member SNRK kinase family as distant relatives of AMPK. However, only one of these is phosphorylated and activated by LKB1. Although much is known about AMPK, many of the AMPK-related kinases remain largely uncharacterized. This review outlines the general similarities in structure and function of the AMPK-related kinases before examining the specific characteristics of each, including a brief discussion of the SNRK family.
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PMID:The regulation and function of mammalian AMPK-related kinases. 1924 55

Par-1 is an evolutionarily conserved protein kinase required for polarity in worms, flies, frogs, and mammals. The mammalian Par-1 family consists of four members. Knockout studies of mice implicate Par-1b/MARK2/EMK in regulating fertility, immune homeostasis, learning, and memory as well as adiposity, insulin hypersensitivity, and glucose metabolism. Here, we report phenotypes of mice null for a second family member (Par-1a/MARK3/C-TAK1) that exhibit increased energy expenditure, reduced adiposity with unaltered glucose handling, and normal insulin sensitivity. Knockout mice were protected against high-fat diet-induced obesity and displayed attenuated weight gain, complete resistance to hepatic steatosis, and improved glucose handling with decreased insulin secretion. Overnight starvation led to complete hepatic glycogen depletion, associated hypoketotic hypoglycemia, increased hepatocellular autophagy, and increased glycogen synthase levels in Par-1a(-/-) but not in control or Par-1b(-/-) mice. The intercrossing of Par-1a(-/-) with Par-1b(-/-) mice revealed that at least one of the four alleles is necessary for embryonic survival. The severity of phenotypes followed a rank order, whereby the loss of one Par-1b allele in Par-1a(-/-) mice conveyed milder phenotypes than the loss of one Par-1a allele in Par-1b(-/-) mice. Thus, although Par-1a and Par-1b can compensate for one another during embryogenesis, their individual disruption gives rise to distinct metabolic phenotypes in adult mice.
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PMID:Loss of Par-1a/MARK3/C-TAK1 kinase leads to reduced adiposity, resistance to hepatic steatosis, and defective gluconeogenesis. 2073 3

Post-translational modification of proteins is a universal form of cellular regulation. Phosphorylation on serine, threonine, tyrosine or histidine residues by protein kinases is the most widespread and versatile form of covalent modification. Resultant changes in activity, localization or stability of phosphoproteins drives cellular events. MS and bioinformatic analyses estimate that ~30% of intracellular proteins are phosphorylated at any given time. Multiple approaches have been developed to systematically define targets of protein kinases; however, it is likely that we have yet to catalogue the full complement of the phosphoproteome. The amino acids that surround a phosphoacceptor site are substrate determinants for protein kinases. For example, basophilic enzymes such as PKA (protein kinase A), protein kinase C and calmodulin-dependent kinases recognize basic side chains preceding the target serine or threonine residues. In the present paper we describe a strategy using peptide arrays and motif-specific antibodies to identify and characterize previously unrecognized substrate sequences for protein kinase A. We found that the protein kinases PKD (protein kinase D) and MARK3 [MAP (microtubule-associated protein)-regulating kinase 3] can both be phosphorylated by PKA. Furthermore, we show that the adapter protein RIL [a product of PDLIM4 (PDZ and LIM domain protein 4)] is a PKA substrate that is phosphorylated on Ser(119) inside cells and that this mode of regulation may control its ability to affect cell growth.
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PMID:Discovery of cellular substrates for protein kinase A using a peptide array screening protocol. 2164 27

The Chk1 protein kinase is activated in response to DNA damage through ATR-mediated phosphorylation at multiple serine-glutamine (SQ) residues within the C-terminal regulatory domain, however the molecular mechanism is not understood. Modelling indicates a high probability that this region of Chk1 contains a kinase-associated 1 (KA1) domain, a small, compact protein fold found in multiple protein kinases including SOS2, AMPK and MARK3. We introduced mutations into Chk1 designed to disrupt specific structural elements of the predicted KA1 domain. Remarkably, six of seven Chk1 KA1 mutants exhibit constitutive biological activity (Chk1-CA) in the absence of DNA damage, profoundly arresting cells in G2 phase of the cell cycle. Cell cycle arrest induced by selected Chk1-CA mutants depends on kinase catalytic activity, which is increased several-fold compared to wild-type, however phosphorylation of the key ATR regulatory site serine 345 (S345) is not required. Thus, mutations targeting the putative Chk1 KA1 domain confer constitutive biological activity by circumventing the need for ATR-mediated positive regulatory phosphorylation.
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PMID:KA1-targeted regulatory domain mutations activate Chk1 in the absence of DNA damage. 2603 76

MAP/Microtubule affinity-regulating kinase 4 (MARK4), a Ser/Thr protein kinases, is related to the Par-1 (partitioning-defective) gene products, and is the human ortholog of Par-1. MARK4 shows its role in the cell polarity at the time of embryonic development. It is mostly located at the basal region of cells, providing apico-basal polarity. Here, we made two variants of human Par-1d (MARK4), kinase domain (MARK4-F2), and kinase domain along with 59 N-terminal residues (MARK4-F1) and saw their ATPase hydrolysis in the presence of each other. We observed that the activity of one variant was increased in the presence of other. We also demonstrated that both variants were phosphorylated by atypical PKC and their activities were increased in the presence of increasing concentration of atypical protein kinase c (aPKC). The phosphorylation was observed at the serine and threonine residues of MARK4. The interaction of MARK2 and MARK3 with aPKC and their negative regulation by aPKC is already known. This study confirms a functional link between aPKC and MARK4, two central determinants of cell polarity, and it suggests that aPKC may regulate all four members of Par-1 through phosphorylating them in polarized cells.
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PMID:Atypical PKC phosphorylates microtubule affinity-regulating kinase 4 in vitro. 2634 60