The reference OMIM entry for this protein is 604666

Mitogen-activated protein kinase kinase kinase kinase 4; map4k4
Hematopoietic progenitor kinase/germinal center kinase-like kinase; hgk
Nck-interacting kinase; nik

CLONING

Activation of the JNK (see 601158) pathway by a variety of environmental and extracellular stimuli is mediated by multiple STE20-like protein kinases (e.g., STK25, 602255). By screening a human macrophage cDNA library with degenerate PCR primers to sequences of STE20 family members, Yao et al. (1999) obtained a novel cDNA that they termed HGK (for HPK1/GCK-like kinase). The HGK cDNA encodes a 1,165-amino acid protein. Its N terminus has a catalytic kinase domain with 11 kinase subdomains. It shares 47% and 48% amino acid sequence identity to the catalytic domain of HPK1 (601983) and GCK (603166), respectively. The authors identified 2 HGK isoforms, one of which has no proline-rich domains, and another, longer variant that contains such domains and appears to be expressed in brain only. Northern blot analysis revealed expression of 3 HGK transcripts of approximately 4.6, 6.5, and 8.5 kb in heart, brain, skeletal muscle, pancreas, placenta, liver, lung, and kidney. By Western blot analysis with a polyclonal antibody, Yao et al. (1999) found that the 130-kD protein is expressed in multiple cell lines. Expression of HGK in transfected cell lines resulted in strong JNK activation and, in turn, c-jun transcriptional activity. HGK-induced JNK activation was inhibited by dominant-negative MKK4 (MAP2K4; 601335), MKK7 (MAP2K7; 603014), and TAK1 (MAP3K7; 602614) mutants. TNFA (191160) also stimulated HGK kinase activity.

GENE FUNCTION

Using an RNA interference-based screen, Tang et al. (2006) found 4 negative regulators of insulin-responsive glucose transport in mouse adipocytes: Pctk1 (311550), Pftk1 (610679), Ikbka (CHUK; 600664), and Map4k4. Map4k4 suppressed expression of adipogenic transcription factors, Cebpa (116897), Cebpb (189965), and Pparg (601487), and it suppressed surface expression of Glut4 (SLC2A4; 138190), resulting in attenuated membrane hexose transport activity. Depletion of Map4k4 by RNA interference early in differentiation enhanced adipogenesis and triglyceride deposition; in fully differentiated adipocytes, loss of Map4k4 upregulated Glut4 expression. Conversely, conditions that inhibited adipogenesis, such as Tnfa treatment or Pparg depletion, markedly upregulated Map4k4. Tang et al. (2006) concluded that MAP4K4-dependent signaling inhibited PPARG-responsive gene expression, adipogenesis, and insulin-stimulated glucose transport. Aouadi et al. (2009) reported the engineering of beta-1,3-D-glucan-encapsulated siRNA particles (GeRPs) as efficient oral delivery vehicles that potently silenced genes in mouse macrophages in vitro and in vivo. Oral gavage of mice with GeRPs containing as little as 20 micrograms per kilogram siRNA directed against TNF-alpha (191160) depleted its mRNA in macrophages recovered from peritoneum, spleen, liver, and lung, and lowered serum TNF-alpha levels. Screening with GeRPs for inflammation genes revealed that Map4k4 is a mediator of cytokine expression. Importantly, silencing Map4k4 in macrophages in vivo protected mice from lipopolysaccharide-induced lethality by inhibiting TNF-alpha and interleukin-1-beta (147720) production. Aouadi et al. (2009) concluded that their technology defined a strategy for oral delivery of siRNA to attenuate inflammatory responses in human disease. Using in vitro angiogenesis screens with short interfering RNA (siRNA) and chemical inhibitors, Vitorino et al. (2015) defined a MAP4K4-moesin (MSN; 309845)-talin (TLN; 186745)-beta-1-integrin ... More on the omim web site

Subscribe to this protein entry history

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 604666 was added.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).