Abstract
Prostate carcinoma (PCA) is the most commonly diagnosed malignancy in American men. Our knowledge of PCA growth regulation lags behind that of other cancers, such as breast and colon carcinomas. Among receptor tyrosine kinases, the ErbB family is most frequently implicated in neoplasia. We report here the expression of ErbB family kinases and their ligands in PCA cell lines and a xenograft. While ErbB1/EGFR, ErbB2/NEU, and ErbB3 were always observed in a distinct pattern, ErbB4 was not observed. Interestingly, while TGF-alpha was expressed in the majority of PCA lines, the ligand Neu Differentiation Factor/Heregulin (NDF) was expressed only in an immortalized, non-transformed prostate epithelial line. Concomitantly, there was a significant difference in biological response to these ligands. NDF inhibited LNCaP growth and induced an epithelial-like morphological change, in contrast to TGF-alpha, which accelerated cell growth. We also performed the first comprehensive analysis of NDF signaling in a prostate line. LNCaP stimulated with NDF demonstrated crosstalk between ErbB3 and ErbB2 which did not involve ErbB1. NDF also turned on several cascades, including those of PI3-K, ERK/MAPK, mHOG/p38 and JNK/SAPK, but not those of PLCgamma or the STAT family. This signaling pattern is distinct from that of TGF-alpha. The activation of mHOG by ErbB2 or ErbB3 has not been reported, and may contribute to the unusual phenotype. PI3-K activation is characterized by the formation of a striking 'activation complex' with multiple tyrosine-phosphorylated species, including ErbB3. Our studies provide a framework in which to dissect the growth and differentiation signals of prostate cancer cells.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Calcium-Calmodulin-Dependent Protein Kinases / drug effects
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Carcinoma / drug therapy
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Carcinoma / genetics
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Carcinoma / metabolism
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Cell Division / drug effects
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DNA-Binding Proteins / drug effects
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DNA-Binding Proteins / metabolism
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Enzyme Activation / drug effects
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ErbB Receptors / drug effects
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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Glycoproteins / genetics
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Glycoproteins / metabolism*
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Glycoproteins / pharmacology
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Humans
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Isoenzymes / drug effects
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Isoenzymes / metabolism
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Male
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Milk Proteins*
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Mitogen-Activated Protein Kinases*
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Neuregulins
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Phosphatidylinositol 3-Kinases / drug effects
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Phosphatidylinositol 3-Kinases / metabolism
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Phospholipase C gamma
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Phosphorylation
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Prostatic Neoplasms / drug therapy
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism*
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Receptor, ErbB-2 / drug effects
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism
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Receptor, ErbB-3
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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STAT5 Transcription Factor
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Signal Transduction
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Trans-Activators / drug effects
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Trans-Activators / metabolism
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Transforming Growth Factor alpha / pharmacology
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Transplantation, Heterologous
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Tumor Cells, Cultured
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Type C Phospholipases / drug effects
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Type C Phospholipases / metabolism
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Tyrosine
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p38 Mitogen-Activated Protein Kinases
Substances
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DNA-Binding Proteins
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Glycoproteins
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Isoenzymes
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Milk Proteins
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Neuregulins
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Proto-Oncogene Proteins
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Recombinant Proteins
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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STAT5 Transcription Factor
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Trans-Activators
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Transforming Growth Factor alpha
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Tyrosine
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Phosphatidylinositol 3-Kinases
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ErbB Receptors
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Receptor, ErbB-2
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Receptor, ErbB-3
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Type C Phospholipases
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Phospholipase C gamma