Disease relevance of MAP4K1

• Furthermore, HPK1-deficient mice were more susceptible to experimental autoimmune encephalomyelitis [1].
• Zerumbone ring-opening derivative 2 inhibited autophosphorylation of the essential histidine protein kinase (HPK), YycG, existing in Bacillus subtilis constituting a two-component system (TCS) [2].

High impact information on MAP4K1

• These results indicate that HPK1 is a novel functional activator of the JNK/SAPK signaling pathway [3].
• We have cloned a novel protein kinase, termed hematopoietic progenitor kinase 1 (HPK1), that is expressed predominantly in hematopoietic cells, including early progenitor cells [3].
• Neither form of HPK1 affected PMA or v-Ras activation of AP-1 and ERK2 [4].
• Engagement of the TCR or the BCR resulted in a marked induction of HPK1 catalytic activity [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 [4].

Biological context of MAP4K1

• TGF-beta treatment resulted in a time-dependent activation of HPK1, which was accompanied by similar kinetics of JNK1 activation [5].
• In addition, interaction between HPK1 and TAK1 was observed in transient transfection assays, and this interaction was enhanced by TGF-beta treatment [5].
• Here, we report that an upstream activator of JNK, hematopoietic progenitor kinase 1 (HPK1), was cleaved during apoptosis [6].
• HPK1 tyrosine phosphorylation and kinase activation depend on the presence of adaptor proteins [7].
• To gain insight into the regulation of leukocyte signal transduction, we investigated the molecular details of HPK1 activation [8].

Anatomical context of MAP4K1

• Taken together, our findings demonstrate the functional interaction of HPK1 with Crk and CrkL, reveal the downstream pathways of Crk- and CrkL-induced JNK activation, and highlight a potential role of HPK1 in T-cell activation [9].
• Thus, activation of major lymphocyte signaling pathways via HPK1 involves (i) relocation, (ii) autophosphorylation, and (iii) transphosphorylation of HPK1 by PKD [8].
• Here we report that the serine/threonine kinase hematopoietic progenitor kinase 1 (HPK1), which is activated upon antigen-receptor stimulation and which has been implicated in the regulation of MAP kinase pathways, interacts physically and functionally with BLNK in B cells and with SLP-76 in T cells [10].
• The results demonstrate that exposure of Jurkat cells to DNA-damaging agents is associated with translocation of active c-Abl from nuclei to cytoplasm and binding of c-Abl to HPK1 [11].
• Using a yeast two-hybrid screen and cotransfection experiments with Cos-1 cells, evidence was adduced that p92 is HPK-1, a serine/threonine-specific protein kinase expressed in hemopoietic cells [12].

Associations of MAP4K1 with chemical compounds

• Interestingly, HPK1 phosphorylated Crk and CrkL, mainly on serine and threonine residues in vitro [9].
• We found that PP4 interacted with HPK1 and that the proline-rich region of HPK1 was necessary and sufficient for this interaction [13].
• By testing HPK1 proteins with in vivo and in vitro cleavage assays, we showed that aspartic acid residue 385 is the target for caspases [6].
• We show that full activation of HPK1 is dependent on autophosphorylation of threonine 165 and phosphorylation of serine 171, which is a target site for protein kinase D (PKD) in vitro [8].
• Hematopoietic progenitor kinase 1 (HPK1) negatively regulates prostaglandin E2-induced fos gene transcription [14].

Physical interactions of MAP4K1

• We found that HPK1 bound to HIP-55 both in vitro and in vivo [15].
• These findings indicate that activation of HPK1 and formation of HPK1/c-Abl complexes are functionally important in the stress response of hematopoietic cells to genotoxic agents [11].
• While KHS bound exclusively to Crk family proteins, HPK1 also interacted with both SH3 domains of Grb2 and weakly with Nck, but not with more than 25 other SH3 domains tested [16].
• A screen for HPK1 binding proteins identified the hematopoietic cell-specific protein 1 (HS1) as a potential HPK1 interaction partner [17].
• We found that Grap2 interacted with the hematopoietic progenitor kinase 1 (HPK1) in vitro and in Jurkat T cells [18].

Regulatory relationships of MAP4K1

• Hematopoietic progenitor kinase 1 is a component of transforming growth factor beta-induced c-Jun N-terminal kinase signaling cascade [5].
• Moreover, we found that the PP4-induced HPK1 kinase activation was accompanied by an increase in protein expression of HPK1 [13].
• Tumorigenesis suppressor Pdcd4 down-regulates mitogen-activated protein kinase kinase kinase kinase 1 expression to suppress colon carcinoma cell invasion [19].
• Thus, HPK1 is a negative regulator of the TCR-induced AP-1 response pathway [4].
• Interestingly, either S376A mutation or HPK-1 knockdown resulted in increased TCR-induced tyrosine phosphorylation of SLP-76 and phospholipase C-gamma1 [20].

Other interactions of MAP4K1

• Interaction of hematopoietic progenitor kinase 1 with adapter proteins Crk and CrkL leads to synergistic activation of c-Jun N-terminal kinase [9].
• Pulse-chase analysis showed that PP4 increased the half-life of HPK1 [13].
• The C-terminal fragment, although having three proline-rich domains, bound to Grb2 and Crk less efficiently than the full-length HPK1 protein [6].
• The HPK1 mutant (HPK1-PR), which encodes the proline-rich region alone, blocked JNK activation by Crk and CrkL [9].
• Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic specific mammalian Ste20-like protein kinase and has been implicated in many cellular signaling pathways including T cell receptor (TCR) signaling [13].

Analytical, diagnostic and therapeutic context of MAP4K1

• BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation [21].
• Using isothermal titration calorimetry and x-ray crystallography, the binding of the HPK1 motif to Mona/Gads SH3C has now been characterized in molecular detail [22].
• In vitro complexes were highly stable and in vivo complexes of c-Crk and CRKL with HPK1 were detectable by co-immunoprecipitation with transiently transfected cells but also with endogenous proteins [16].
• The germinal center kinase (GCK)-related protein kinases HPK1 and KHS are candidates for highly selective signal transducers of Crk family adapter proteins [16].

References