PMID- 10471319
OWN - NLM
STAT- MEDLINE
DCOM- 19991005
LR  - 20191210
IS  - 0014-4827 (Print)
IS  - 0014-4827 (Linking)
VI  - 251
IP  - 2
DP  - 1999 Sep 15
TI  - PI3-kinase is involved in mitogenic signaling by the oncogenic receptor tyrosine 
      kinase Xiphophorus melanoma receptor kinase in fish melanoma.
PG  - 340-9
AB  - Overexpression of the mutationally activated receptor tyrosine kinase Xiphophorus
      melanoma receptor kinase (Xmrk) initiates formation of hereditary malignant
      melanoma in the fish Xiphophorus. In melanoma as well as in a melanoma-derived
      cell line (PSM) this receptor is highly activated resulting in constitutive
      Xmrk-mediated mitogenic signaling. In order to analyze mitogenic signaling
      triggered by Xmrk a possible involvement of phosphatidylinositol 3 (PI3)-kinase
      in Xmrk signal transduction was examined. Constitutive binding of the p85 adapter
      subunit of PI3-kinase to the Xmrk receptor was detected in PSM melanoma cells.
      Further analyses in BHK cells expressing a Xmrk chimera (HER-mrk) showed that p85
      association with the intracellular part of Xmrk was dependent on
      autophosphorylation of the receptor. In vitro binding studies revealed that the
      interaction is mediated mainly through the N-terminal SH2 domain of p85 which
      directly binds to a sequence motif around phosphorylated Tyr-983 in the Xmrk
      carboxy-terminus. In accordance with recruitment of p85 by Xmrk in PSM cells, the
      PI3-kinase downstream target Akt was found to be highly phosphorylated on
      Ser-473, indicating efficient PI3-kinase signaling in melanoma cells. PI3-kinase 
      activation was also detected in Xiphophorus melanoma. Moreover, malignant
      melanomas exhibited an increased level of PI3-kinase activity which was about
      three times higher than that in benign pigmented lesions. Inhibition of
      PI3-kinase activity in PSM melanoma cells by both Wortmannin and LY294002 blocked
      entry into S-phase. Together these data demonstrate that PI3-kinase is a
      substrate of the oncogenic Xmrk receptor and plays a significant role in
      mitogenic signaling of melanoma cells and the formation of malignant melanoma in 
      Xiphophorus.
CI  - Copyright 1999 Academic Press.
FAU - Wellbrock, C
AU  - Wellbrock C
AD  - Biocenter (Theodor-Boveri Institut), University of Wurzburg, Wurzburg, Germany.
      wellbrock@biozentrum.uni-wuerzburg.de
FAU - Fischer, P
AU  - Fischer P
FAU - Schartl, M
AU  - Schartl M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Exp Cell Res
JT  - Experimental cell research
JID - 0373226
RN  - 0 (Androstadienes)
RN  - 0 (Chromones)
RN  - 0 (Fish Proteins)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Xmrk protein, Xiphophorus)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Amino Acid Sequence
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Binding Sites
MH  - Chromones/pharmacology
MH  - Enzyme Activation
MH  - *Fish Proteins
MH  - Fishes
MH  - Melanoma, Experimental/enzymology/etiology/*metabolism
MH  - Mitosis
MH  - Molecular Sequence Data
MH  - Morpholines/pharmacology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Binding
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Receptor Protein-Tyrosine Kinases/*metabolism
MH  - Signal Transduction
MH  - Tumor Cells, Cultured
MH  - Wortmannin
EDAT- 1999/09/02 00:00
MHDA- 1999/09/02 00:01
CRDT- 1999/09/02 00:00
PHST- 1999/09/02 00:00 [pubmed]
PHST- 1999/09/02 00:01 [medline]
PHST- 1999/09/02 00:00 [entrez]
AID - 10.1006/excr.1999.4580 [doi]
AID - S0014-4827(99)94580-9 [pii]
PST - ppublish
SO  - Exp Cell Res. 1999 Sep 15;251(2):340-9. doi: 10.1006/excr.1999.4580.