PMID- 10353604
OWN - NLM
STAT- MEDLINE
DCOM- 19990617
LR  - 20181201
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 18
IP  - 16
DP  - 1999 Apr 22
TI  - Characterization of a naturally occurring ErbB4 isoform that does not bind or
      activate phosphatidyl inositol 3-kinase.
PG  - 2607-15
AB  - Receptor tyrosine kinases regulate cell behavior by activating specific signal
      transduction cascades. Epidermal growth factor (EGF) receptor tyrosine kinases
      include ErbB1, ErbB2, ErbB3 and ErbB4. ErbB4 is a tyrosine kinase receptor that
      binds neuregulins (NRG) and several other EGF family members. Reverse
      transcriptase polymerase chain reaction (RT-PCR) analysis identified two isoforms
      of ErbB4 that differed in their cytoplasmic domain sequences. Specifically,
      RT-PCR using primers flanking the putative phosphatidyl inositol 3-kinase (PI3-K)
      binding site of ErbB4 generated two specific bands when human and mouse heart and
      kidney tissues were analysed. Cloning and sequencing of these RT-PCR products
      revealed that one of the ErbB4 isoforms (ErbB4 CYT-2) lacked a 16 amino acid
      sequence including a putative PI3-K binding site, that was present in the other
      isoform (ErbB4 CYT-1). RT-PCR analysis of mouse tissues suggested that the
      expression of ErbB4 CYT-1 and ErbB4 CYT-2 was tissue-specific. Heart, breast and 
      abdominal aorta expressed predominantly ErbB4 CYT-1 whereas neural tissues and
      kidney expressed predominantly ErbB4 CYT-2. To ascertain whether the absence of
      the putative PI3-K binding site in ErbB4 CYT-2 also resulted in the loss of PI3-K
      activity, NIH3T3 cell lines overexpressing ErbB4 CYT-1 or ErbB4 CYT-2 were
      produced. NRG-1 bound to and stimulated equivalent tyrosine phosphorylation of
      both isoforms. However, unlike ErbB4 CYT-1, the ErbB4 CYT-2 isoform was unable to
      bind the p85 subunit of PI3-K and to stimulate PI3-K activity in these cells.
      Furthermore, tyrosine phosphorylation of p85 or association of PI3-K activity
      with phosphotyrosine was not induced in NRG-1 treated cells expressing ErbB4
      CYT-2, indicating that this isoform was incapable of activating PI3-K even
      indirectly. It was concluded that a novel naturally occurring ErbB4 isoform
      exists with a deletion of the cytoplasmic domain sequence required for the
      activation of the PI3-K intracellular signal transduction pathway and that this
      is the only PI3-K binding site in ErbB4.
FAU - Elenius, K
AU  - Elenius K
AD  - Department of Surgery, Children's Hospital and Harvard Medical School, Boston, MA
      02115, USA.
FAU - Choi, C J
AU  - Choi CJ
FAU - Paul, S
AU  - Paul S
FAU - Santiestevan, E
AU  - Santiestevan E
FAU - Nishi, E
AU  - Nishi E
FAU - Klagsbrun, M
AU  - Klagsbrun M
LA  - eng
GR  - CA 37392/CA/NCI NIH HHS/United States
GR  - GM 47397/GM/NIGMS NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Protein Isoforms)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.10.1 (ERBB4 protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Erbb4 protein, mouse)
RN  - EC 2.7.10.1 (Receptor, ErbB-4)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Base Sequence
MH  - Cytoplasm/enzymology
MH  - Enzyme Activation
MH  - ErbB Receptors/*metabolism
MH  - Humans
MH  - Mice
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Protein Binding
MH  - Protein Isoforms/metabolism
MH  - Receptor, ErbB-4
MH  - Sequence Analysis, DNA
MH  - Sequence Homology, Amino Acid
EDAT- 1999/06/03 00:00
MHDA- 1999/06/03 00:01
CRDT- 1999/06/03 00:00
PHST- 1999/06/03 00:00 [pubmed]
PHST- 1999/06/03 00:01 [medline]
PHST- 1999/06/03 00:00 [entrez]
AID - 10.1038/sj.onc.1202612 [doi]
PST - ppublish
SO  - Oncogene. 1999 Apr 22;18(16):2607-15. doi: 10.1038/sj.onc.1202612.