Tyrosine phosphorylation of HPK1 by activated Src promotes ischemic brain injury in rat hippocampal CA1 region.
Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted member of the Ste20 serine/threonine kinase super family. We recently reported that HPK1 is involved in c-Jun NH2-terminal kinase (JNK) signaling pathway by sequential activation of MLK3-MKK7-JNK3 after cerebral ischemia. Here, we used 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d] pyrimidine (PP2) and MK801 to investigate the events upstream of HPK1 in ischemic brain injury. Immunoprecipitation and immunoblot results showed that PP2 and MK801 significantly decreased the activation of Src, HPK1, MLK3, JNK3 and c-Jun, respectively, during ischemia/reperfusion. Histology and TUNEL staining showed PP2 or MK801 protects against neuron death after brain ischemia. We speculate that this unique signaling pathway through the tyrosine phosphorylation of HPK1 promotes ischemic brain injury by activated Src via N-methyl-d-aspartate receptor and, ultimately, the activation of the MLK3-MKK7-JNK3 pathway after cerebral ischemia.
Li
Ting
T
Research Center for Biochemistry and Molecular Biology, Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, 84 West Huaihai Road, Xuzhou, Jiangsu 221002, China.
Yu
Xiu-Ju
XJ
Zhang
Guang-Yi
GY
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D019610:Cytoprotection; D016291:Dizocilpine Maleate / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D016291:Dizocilpine Maleate; D020930:MAP Kinase Kinase Kinases; D048057:Mitogen-Activated Protein Kinase 10; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines; D014443:Tyrosine; D019061:src-Family Kinases; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C412373:AG 1879; C102102:hematopoietic progenitor kinase 1