EGF or PDGF receptors activate atypical PKClambda through phosphatidylinositol 3-kinase.
Overexpression of a TPA-insensitive PKC member, an atypical protein kinase C (aPKClambda), results in an enhancement of the transcriptional activation of TPA response element (TRE) in cells stimulated with epidermal growth factor (EGF) or platelet-derived growth factor (PDGF). EGF or PDGF also caused a transient increase in the in vivo phosphorylation level and a change in the intracellular localization of aPKClambda from the nucleus to the cytosol, indicating the activation of aPKClambda in response to this growth factor stimulation. These immediate signal-dependent changes in aKPClambda were observed for a PDGF receptor add-back mutant (Y40/51) that possesses only two of the five major autophosphorylation sites and binds PI3-kinase, and were inhibited by wortmannin, an inhibitor of PI3-kinase. Furthermore, an N-terminal fragment of the catalytic subunit of PI3-kinase, p110alpha, inhibited aPKClambda-dependent activation of TRE in Y40/51 cells stimulated with PDGF. Overexpression of p110alpha resulted in an enhancement of TRE expression in response to PDGF and the regulatory domain of aPKClambda inhibited this TRE activation in Y40/51 cells. These results provide the first in vivo evidence supporting the presence of a novel signalling pathway from receptor tyrosine kinases to aPKClambda through PI3-kinase.
Akimoto
K
K
Department of Molecular Biology, Yokohama City University School of Medicine, Japan.
Takahashi
R
R
Moriya
S
S
Nishioka
N
N
Takayanagi
J
J
Kimura
K
K
Fukui
Y
Y
Osada
S i
Si
Mizuno
K
K
Hirai
S i
Si
Kazlauskas
A
A
Ohno
S
S
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002451:Cell Compartmentation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000502:physiology*; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D014158:Transcription, Genetic
D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D019000:Phosphotyrosine; D011493:Protein Kinase C; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor