A novel six-transmembrane protein hhole functions as a suppressor in MAPK signaling pathways.
Src homology 3 (SH3) domains mediate intracellular protein-protein interactions through the recognition of proline-rich sequence motifs on cellular proteins. Such protein-protein interactions can activate the protein kinase cascade that mediates MAPK signaling pathway. The human hole gene, hhole, is a 319-amino acid six-transmembrane protein with proline-rich C-terminal motifs and N-terminal ERK binding domains (D-domains). The hhole protein is highly conserved in evolution across different species from elegent, mouse to human. Northern blot analysis indicates that hhole is expressed in heart, liver, skeletal muscle, and pancreas at adult stages and in most of the examined embryonic tissues, especially at a higher level in heart. Using a GFP-labeled hhole protein, we demonstrate that hhole is localized in plasma membrane or proximal region of the membrane. Overexpression of hhole in COS-7 cells strongly inhibited the transcriptional activities of AP-1 and SRE while deletion of the C-terminal proline-rich motifs or the N-terminal ERK binding D-domain motifs reduced the repressive activity of the gene. These results suggest that the hhole protein may interact with SH3-domain proteins or ERKs to mediate signaling pathways/networks that lead to the suppression of AP-1 and SRE.
Zhou
Junmei
J
The Center for Heart Development, College of Life Sciences, Hunan Normal University, Changsha, 410081 Hunan, People's Republic of China.
Li
Yongqing
Y
Liang
Pei
P
Yuan
Wuzhou
W
Ye
Xiangli
X
Zhu
Chuanbing
C
Cheng
Yingduan
Y
Wang
Yuequn
Y
Li
Guan
G
Wu
Xiushan
X
Liu
Mingyao
M
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000032:analysis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D009928:Organ Specificity; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology*; D014018:Tissue Distribution; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology; D018909:src Homology Domains
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011994:Recombinant Proteins; C502774:SRE protein, human; C503401:TMEM121 protein, human; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases