Disease relevance of MAP4K2

• Study of 260 subjects with glucokinase-deficient hyperglycaemia from 42 families with 36 different GCK mutations made it possible to define the clinical profile of this subtype of non-insulin-dependent diabetes mellitus (NIDDM) [1].
• A stepwise forward selection procedure demonstrated that ACE, GCK, and ESR1 genotypes significantly (P<0.01) and independently affected the prevalence of obesity [2].
• Two children of Group A (5%) were found to be affected by fasting hyperglycemia and carry a GCK gene mutation that in one case was present also in the diabetic father [3].

High impact information on MAP4K2

• Here we report specific activation of the mammalian stress-activated protein kinase (SAPK) pathway by germinal centre kinase (GCK), a human STE20 homologue [4].
• Although GCK is found in many tissues, its expression in lymphoid follicles is restricted to the cells of the germinal centre, where it may participate in B-cell differentiation [4].
• The serine/threonine kinase HPK1 is a member of the germinal center kinase (GCK) family that has been implicated in the regulation of MAP kinase pathways [5].
• Like the GC kinase, rab8ip has protein kinase activity manifested by autophosphorylation and phosphorylation of the classical serine/threonine protein kinase substrates, myelin basic protein and casein [6].
• Here we report the identification and the complete cDNA-derived amino acid sequence of a murine rab8-interacting protein (rab8ip) that specifically interacts with rab8 in a GTP-dependent manner [6].

Biological context of MAP4K2

• GC kinase may participate in an important signal transduction pathway in germinal center B cells [7].
• The nucleotide sequence of a 2,874-base pair BL44 cDNA was determined and a 2,451-bp open reading frame found that encodes for a 97-kDa serine/threonine protein kinase referred to as GC kinase [7].
• Moreover, the GCK -30A allele frequency was higher among 2,587 subjects with impaired glucose regulation (IGR) than among 4,773 glucose-tolerant subjects (17.3% [95% CI 16.2-18.3] vs. 15.0% [14.3-15.7], P < 0.001, odds ratio GG vs. GA 1.21 [1.08-1.36], GG vs. AA 1.62 [1.17-2.24]) [8].
• The promotor and coding regions inclusive intron exon boundaries of the HNF-4alpha, GCK and HNF-1alpha genes were examined by PCR-dHPLC (HNF-1alpha and GCK) and direct sequencing [9].
• Genetic epidemiology of MODY in the Czech republic: new mutations in the MODY genes HNF-4alpha, GCK and HNF-1alpha [9].

Anatomical context of MAP4K2

• We have isolated a cDNA encoding a novel protein kinase that has significant sequence similarities to human germinal center kinase (GCK) and human hematopoietic progenitor kinase 1 [10].
• This is the first time that a GCK family kinase is shown to be potentially involved in the regulation of cytoskeleton [11].
• The GC kinase protein was immunoprecipitated from transfected COS cells and from the Burkitt cell line RAMOS [7].
• Collectively, these results showed that increases in SREBP-1c were neither necessary nor sufficient for GCK induction in hepatocytes, while at the same time they underscored the role of SREBP-1c as a key regulator of FASN [12].

Associations of MAP4K2 with chemical compounds

• Although curcumin suppressed TAK1 and GCK activities at high concentrations, this inhibition cannot fully account for the JNK inhibition by curcumin in vivo [13].
• CONCLUSIONS: These data support the association between carriage of GCK gene mutations, G264S and IVS8+2, and the development of diabetes, impaired fasting glucose and reduced birthweight [14].

Other interactions of MAP4K2

• However, in contrast to other GCKs, this activation is mediated solely by the GCK homology region of TNIK [11].
• Here, we report that Bcr-Abl through a Ras-dependent pathway signals the serine/threonine protein kinase GCKR (Germinal Center Kinase Related) leading to SAPK activation [15].

Analytical, diagnostic and therapeutic context of MAP4K2

• Treatment of hepatocytes with insulin and/or T0901317 resulted in the recruitment of SREBP-1c to the FASN promoter as shown by chromatin immunoprecipitation, whereas SREBP-1c did not bind to the GCK promoter [12].
• The GCK -30G>A polymorphism was genotyped in the population-based Inter99 study cohort (5,965 subjects) and in 332 nondiabetic subjects and 1,063 patients with type 2 diabetes [8].
• The promotor and coding regions including intron-exon boundaries of HNF4A, GCK, and TCF1 were examined by denaturing HPLC and/or direct sequencing [16].

References