HPK1 is activated by lymphocyte antigen receptors and negatively regulates AP-1.
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. Here, we demonstrate the involvement of HPK1 in antigen receptor signaling. Engagement of the TCR or the BCR resulted in a marked induction of HPK1 catalytic activity. Subsequent analysis revealed that Src and Syk/ZAP-70 tyrosine kinases and the adaptor proteins LAT, SLP-76, BLNK, Grb2, and Grap are involved in HPK1 activation. Overexpression of HPK1 inhibited TCR activation of AP-1 and ERK2, whereas the kinase-inactive mutant of HPK1 potentiated these responses. Neither form of HPK1 affected PMA or v-Ras activation of AP-1 and ERK2. Thus, HPK1 is a negative regulator of the TCR-induced AP-1 response pathway.
Liou
J
J
Department of Medicine, Howard Hughes Medical Institute, University of California, San Francisco 94143, USA.
Kiefer
F
F
Dang
A
A
Hashimoto
A
A
Cobb
M H
MH
Kurosaki
T
T
Weiss
A
A
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000502:physiology; D002384:Catalysis; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein; D006801:Humans; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011506:Proteins / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D051746:ZAP-70 Protein-Tyrosine Kinase; D019061:src-Family Kinases / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C409587:GRAP2 protein, human; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C510602:Grap protein, human; C110810:LAT protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; D011506:Proteins; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell; C092947:SLP-76 signal Transducing adaptor proteins; D018808:Transcription Factor AP-1; C102102:hematopoietic progenitor kinase 1; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D015689:Oncogene Protein p21(ras)