Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK

Genes Dev. 2004 Apr 1;18(7):816-29. doi: 10.1101/gad.1170604.

Abstract

The c-myb proto-oncogene product (c-Myb) regulates both the proliferation and apoptosis of hematopoietic cells by inducing the transcription of a group of target genes. However, the biologically relevant molecular mechanisms that regulate c-Myb activity remain unclear. Here we report that c-Myb protein is phosphorylated and degraded by Wnt-1 signal via the pathway involving TAK1 (TGF-beta-activated kinase), HIPK2 (homeodomain-interacting protein kinase 2), and NLK (Nemo-like kinase). Wnt-1 signal causes the nuclear entry of TAK1, which then activates HIPK2 and the mitogen-activated protein (MAP) kinase-like kinase NLK. NLK binds directly to c-Myb together with HIPK2, which results in the phosphorylation of c-Myb at multiple sites, followed by its ubiquitination and proteasome-dependent degradation. Furthermore, overexpression of NLK in M1 cells abrogates the ability of c-Myb to maintain the undifferentiated state of these cells. The down-regulation of Myb by Wnt-1 signal may play an important role in a variety of developmental steps.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / metabolism*
  • Chloramphenicol O-Acetyltransferase / metabolism
  • Down-Regulation
  • Glutathione Transferase / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Leukemia, Myeloid / metabolism
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mitogens
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Precipitin Tests
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-myb / antagonists & inhibitors
  • Proto-Oncogene Proteins c-myb / metabolism*
  • RNA, Small Interfering / pharmacology
  • Saccharomyces cerevisiae
  • Signal Transduction*
  • Two-Hybrid System Techniques
  • Ubiquitin
  • Wnt Proteins
  • Wnt1 Protein
  • Zebrafish Proteins*

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • MAS1 protein, human
  • Mitogens
  • Nuclear Proteins
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myb
  • RNA, Small Interfering
  • Ubiquitin
  • WNT1 protein, human
  • Wnt Proteins
  • Wnt1 Protein
  • Wnt1 protein, mouse
  • Zebrafish Proteins
  • Chloramphenicol O-Acetyltransferase
  • Glutathione Transferase
  • HIPK2 protein, human
  • Hipk2 protein, mouse
  • NLK protein, human
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7