Heregulin-dependent Activation of Phosphoinositide 3-Kinase and Akt via the ErbB2/ErbB3 Co-receptor

The ErbB2/ErbB3 heregulin co-receptor has been shown to couple to phosphoinositide (PI) 3-kinase in a heregulin-dependent manner. The recruitment and activation of PI 3-kinase by this co-receptor is presumed to occur via its interaction with phosphorylated Tyr-Xaa-Xaa-Met (Y XXM) motifs occurring in...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-11, Vol.276 (45), p.42153-42161
Main Authors: Hellyer, Nathan J., Kim, Myong-Soo, Koland, John G.
Format: Article
Language:English
Subjects:
3T3 Cells
Akt protein
Amino Acid Motifs
Animals
Binding Sites
Biological Transport
COS Cells
Enzyme Activation
ErbB2 protein
heregulin
Mice
Neu protein
Neuregulin-1 - physiology
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation
Precipitin Tests
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
Receptor, ErbB-2 - physiology
Receptor, ErbB-3 - physiology
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Summary:The ErbB2/ErbB3 heregulin co-receptor has been shown to couple to phosphoinositide (PI) 3-kinase in a heregulin-dependent manner. The recruitment and activation of PI 3-kinase by this co-receptor is presumed to occur via its interaction with phosphorylated Tyr-Xaa-Xaa-Met (Y XXM) motifs occurring in the ErbB3 C terminus. In this study, mutant ErbB3 receptor proteins expressed in COS7 cells were used to investigate PI 3-kinase-dependent signaling pathways activated by the ErbB2/ErbB3 co-receptor. We observed that a mutant ErbB3 protein with each of its six Y XXM motifs containing a Tyr → Phe substitution was unable to bind either the p85 regulatory or p110 catalytic subunit of PI 3-kinase. However, restoration of a single Y XXM motif was sufficient to mediate association with the PI 3-kinase holoenzyme, although at a lower level than wild-type ErbB3. When ErbB3 Y XXM motifs were restored in pairs, evidence for cooperativity between two, those incorporating Tyr-1273 and Tyr-1286, was observed. Interestingly, we have shown that an apparent association of PI 3-kinase activity with ErbB2/Neu was due to the residual presence of ErbB3 in ErbB2 immunoprecipitates. The necessity of ErbB3 association with PI 3-kinase for downstream signaling to the effector kinase Akt was also investigated. Here, the heregulin-dependent translocation of Akt to the plasma membrane and its subsequent activation was observed in intact NIH-3T3 fibroblasts. Recruitment of PI 3-kinase to ErbB3 was required for both activities, and it appeared that ErbB2 activation alone was not sufficient to activate PI 3-kinase signaling in these cells.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M102079200