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Development of Erasin: a chromone-based STAT3 inhibitor which induces apoptosis in Erlotinib-resistant lung cancer cells.
Lis C, Rubner S, Roatsch M, Berg A, Gilcrest T, Fu D, Nguyen E, Schmidt AM, Krautscheid H, Meiler J, Berg T
(2017) Sci Rep 7: 17390
MeSH Terms: Antineoplastic Agents, Apoptosis, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Humans, Lung Neoplasms, Molecular Docking Simulation, Phosphorylation, Protein Processing, Post-Translational, STAT1 Transcription Factor, STAT3 Transcription Factor, STAT5 Transcription Factor, Structure-Activity Relationship, Tumor Suppressor Proteins, src Homology Domains
Show Abstract · Added March 17, 2018
Inhibition of protein-protein interactions by small molecules offers tremendous opportunities for basic research and drug development. One of the fundamental challenges of this research field is the broad lack of available lead structures from nature. Here, we demonstrate that modifications of a chromone-based inhibitor of the Src homology 2 (SH2) domain of the transcription factor STAT5 confer inhibitory activity against STAT3. The binding mode of the most potent STAT3 inhibitor Erasin was analyzed by the investigation of structure-activity relationships, which was facilitated by chemical synthesis and biochemical activity analysis, in combination with molecular docking studies. Erasin inhibits tyrosine phosphorylation of STAT3 with selectivity over STAT5 and STAT1 in cell-based assays, and increases the apoptotic rate of cultured NSCLC cells in a STAT3-dependent manner. This ability of Erasin also extends to HCC-827 cells with acquired resistance against Erlotinib, a clinically used inhibitor of the EGF receptor. Our work validates chromone-based acylhydrazones as privileged structures for antagonizing STAT SH2 domains, and demonstrates that apoptosis can be induced in NSCLC cells with acquired Erlotinib resistance by direct inhibition of STAT3.
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15 MeSH Terms
ErbB3 drives mammary epithelial survival and differentiation during pregnancy and lactation.
Williams MM, Vaught DB, Joly MM, Hicks DJ, Sanchez V, Owens P, Rahman B, Elion DL, Balko JM, Cook RS
(2017) Breast Cancer Res 19: 105
MeSH Terms: Alleles, Animals, Breast, Cell Differentiation, Cell Proliferation, Cell Survival, Epithelial Cells, Female, Gene Knockout Techniques, Immunohistochemistry, Lactation, Mice, Mice, Transgenic, Phosphatidylinositol 3-Kinases, Pregnancy, Proto-Oncogene Proteins c-akt, RNA, Messenger, Receptor, ErbB-3, Receptor, ErbB-4, STAT5 Transcription Factor, Signal Transduction
Show Abstract · Added March 14, 2018
BACKGROUND - During pregnancy, as the mammary gland prepares for synthesis and delivery of milk to newborns, a luminal mammary epithelial cell (MEC) subpopulation proliferates rapidly in response to systemic hormonal cues that activate STAT5A. While the receptor tyrosine kinase ErbB4 is required for STAT5A activation in MECs during pregnancy, it is unclear how ErbB3, a heterodimeric partner of ErbB4 and activator of phosphatidyl inositol-3 kinase (PI3K) signaling, contributes to lactogenic expansion of the mammary gland.
METHODS - We assessed mRNA expression levels by expression microarray of mouse mammary glands harvested throughout pregnancy and lactation. To study the role of ErbB3 in mammary gland lactogenesis, we used transgenic mice expressing WAP-driven Cre recombinase to generate a mouse model in which conditional ErbB3 ablation occurred specifically in alveolar mammary epithelial cells (aMECs).
RESULTS - Profiling of RNA from mouse MECs isolated throughout pregnancy revealed robust Erbb3 induction during mid-to-late pregnancy, a time point when aMECs proliferate rapidly and undergo differentiation to support milk production. Litters nursed by ErbB3 dams weighed significantly less when compared to litters nursed by ErbB3 dams. Further analysis revealed substantially reduced epithelial content, decreased aMEC proliferation, and increased aMEC cell death during late pregnancy. Consistent with the potent ability of ErbB3 to activate cell survival through the PI3K/Akt pathway, we found impaired Akt phosphorylation in ErbB3 samples, as well as impaired expression of STAT5A, a master regulator of lactogenesis. Constitutively active Akt rescued cell survival in ErbB3-depleted aMECs, but failed to restore STAT5A expression or activity. Interestingly, defects in growth and survival of ErbB3 aMECs as well as Akt phosphorylation, STAT5A activity, and expression of milk-encoding genes observed in ErbB3 MECs progressively improved between late pregnancy and lactation day 5. We found a compensatory upregulation of ErbB4 activity in ErbB3 mammary glands. Enforced ErbB4 expression alleviated the consequences of ErbB3 ablation in aMECs, while combined ablation of both ErbB3 and ErbB4 exaggerated the phenotype.
CONCLUSIONS - These studies demonstrate that ErbB3, like ErbB4, enhances lactogenic expansion and differentiation of the mammary gland during pregnancy, through activation of Akt and STAT5A, two targets crucial for lactation.
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21 MeSH Terms
Bortezomib augments lymphocyte stimulatory cytokine signaling in the tumor microenvironment to sustain CD8+T cell antitumor function.
Pellom ST, Dudimah DF, Thounaojam MC, Uzhachenko RV, Singhal A, Richmond A, Shanker A
(2017) Oncotarget 8: 8604-8621
MeSH Terms: Adenocarcinoma, Animals, Antineoplastic Agents, Bortezomib, Breast Neoplasms, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Cytokines, Female, Fibrosarcoma, Kidney Neoplasms, Lung Neoplasms, Lymphocytes, Tumor-Infiltrating, Mice, Inbred BALB C, Mice, Transgenic, Phosphatidylinositol 3-Kinase, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Proto-Oncogene Proteins c-akt, Receptors, Cytokine, STAT5 Transcription Factor, Signal Transduction, Tumor Escape, Tumor Microenvironment
Show Abstract · Added March 14, 2017
Tumor-induced immune tolerance poses a major challenge for therapeutic interventions aimed to manage cancer. We explored approaches to overcome T-cell suppression in murine breast and kidney adenocarcinomas, and lung fibrosarcoma expressing immunogenic antigens. We observed that treatment with a reversible proteasome inhibitor bortezomib (1 mg/kg body weight) in tumor-bearing mice significantly enhanced the expression of lymphocyte-stimulatory cytokines IL-2, IL-12, and IL-15. Notably, bortezomib administration reduced pulmonary nodules of mammary adenocarcinoma 4T1.2 expressing hemagglutinin (HA) model antigen (4T1HA) in mice. Neutralization of IL-12 and IL-15 cytokines with a regimen of blocking antibodies pre- and post-adoptive transfer of low-avidity HA518-526-specific CD8+T-cells following intravenous injection of 4T1HA cells increased the number of pulmonary tumor nodules. This neutralization effect was counteracted by the tumor metastasis-suppressing action of bortezomib treatments. In bortezomib-treated 4T1HA tumor-bearing mice, CD4+T-cells showed increased IL-2 production, CD11c+ dendritic cells showed increased IL-12 and IL-15 production, and HA-specific activated CD8+T-cells showed enhanced expression of IFNγ, granzyme-B and transcription factor eomesodermin. We also noted a trend of increased expression of IL-2, IL-12 and IL-15 receptors as well as increased phosphorylation of STAT5 in tumor-infiltrating CD8+T-cells following bortezomib treatment. Furthermore, bortezomib-treated CD8+T-cells showed increased phosphorylation of mitogen-activated protein kinase p38, and Akt, which was abrogated by phosphatidylinositide 3-kinase (PI3K) inhibitor. These data support the therapeutic potential of bortezomib in conjunction with other immunotherapies to augment the strength of convergent signals from CD8+T-cell signaling molecules including TCR, cytokine receptors and downstream PI3K/Akt/STAT5 pathways to sustain CD8+T-cell effector function in the tumor microenvironment.
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24 MeSH Terms
Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling.
Myklebust JH, Brody J, Kohrt HE, Kolstad A, Czerwinski DK, Wälchli S, Green MR, Trøen G, Liestøl K, Beiske K, Houot R, Delabie J, Alizadeh AA, Irish JM, Levy R
(2017) Blood 129: 759-770
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, CD79 Antigens, Diagnosis, Differential, Flow Cytometry, Gene Expression Regulation, Neoplastic, Humans, Immunoglobulin M, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Follicular, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Mantle-Cell, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Phospholipase C gamma, Phosphoproteins, Phosphorylation, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-akt, Receptors, Antigen, B-Cell, STAT1 Transcription Factor, STAT5 Transcription Factor, Signal Transduction, Single-Cell Analysis, Syk Kinase, p38 Mitogen-Activated Protein Kinases, src-Family Kinases
Show Abstract · Added December 31, 2016
Kinases downstream of B-cell antigen receptor (BCR) represent attractive targets for therapy in non-Hodgkin lymphoma (NHL). As clinical responses vary, improved knowledge regarding activation and regulation of BCR signaling in individual patients is needed. Here, using phosphospecific flow cytometry to obtain malignant B-cell signaling profiles from 95 patients representing 4 types of NHL revealed a striking contrast between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) tumors. Lymphoma cells from diffuse large B-cell lymphoma patients had high basal phosphorylation levels of most measured signaling nodes, whereas follicular lymphoma cells represented the opposite pattern with no or very low basal levels. MCL showed large interpatient variability in basal levels, and elevated levels for the phosphorylated forms of AKT, extracellular signal-regulated kinase, p38, STAT1, and STAT5 were associated with poor outcome. CLL tumors had elevated basal levels for the phosphorylated forms of BCR-signaling nodes (Src family tyrosine kinase, spleen tyrosine kinase [SYK], phospholipase Cγ), but had low α-BCR-induced signaling. This contrasted MCL tumors, where α-BCR-induced signaling was variable, but significantly potentiated as compared with the other types. Overexpression of CD79B, combined with a gating strategy whereby signaling output was directly quantified per cell as a function of CD79B levels, confirmed a direct relationship between surface CD79B, immunoglobulin M (IgM), and IgM-induced signaling levels. Furthermore, α-BCR-induced signaling strength was variable across patient samples and correlated with BCR subunit CD79B expression, but was inversely correlated with susceptibility to Bruton tyrosine kinase (BTK) and SYK inhibitors in MCL. These individual differences in BCR levels and signaling might relate to differences in therapy responses to BCR-pathway inhibitors.
© 2017 by The American Society of Hematology.
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26 MeSH Terms
Deep phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment.
Kordasti S, Costantini B, Seidl T, Perez Abellan P, Martinez Llordella M, McLornan D, Diggins KE, Kulasekararaj A, Benfatto C, Feng X, Smith A, Mian SA, Melchiotti R, de Rinaldis E, Ellis R, Petrov N, Povoleri GA, Chung SS, Thomas NS, Farzaneh F, Irish JM, Heck S, Young NS, Marsh JC, Mufti GJ
(2016) Blood 128: 1193-205
MeSH Terms: Adult, Aged, Anemia, Aplastic, Female, Forkhead Transcription Factors, Humans, Immunologic Memory, Immunosuppression, Interleukin-2, Interleukin-7 Receptor alpha Subunit, Leukocyte Common Antigens, Male, Middle Aged, Receptors, CCR4, STAT5 Transcription Factor, T-Lymphocytes, Regulatory, fas Receptor
Show Abstract · Added June 10, 2016
Idiopathic aplastic anemia (AA) is an immune-mediated and serious form of bone marrow failure. Akin to other autoimmune diseases, we have previously shown that in AA regulatory T cells (Tregs) are reduced in number and function. The aim of this study was to further characterize Treg subpopulations in AA and investigate the potential correlation between specific Treg subsets and response to immunosuppressive therapy (IST) as well as their in vitro expandability for potential clinical use. Using mass cytometry and an unbiased multidimensional analytical approach, we identified 2 specific human Treg subpopulations (Treg A and Treg B) with distinct phenotypes, gene expression, expandability, and function. Treg B predominates in IST responder patients, has a memory/activated phenotype (with higher expression of CD95, CCR4, and CD45RO within FOXP3(hi), CD127(lo) Tregs), expresses the interleukin-2 (IL-2)/STAT5 pathway and cell-cycle commitment genes. Furthermore, in vitro-expanded Tregs become functional and take on the characteristics of Treg B. Collectively, this study identifies human Treg subpopulations that can be used as predictive biomarkers for response to IST in AA and potentially other autoimmune diseases. We also show that Tregs from AA patients are IL-2-sensitive and expandable in vitro, suggesting novel therapeutic approaches such as low-dose IL-2 therapy and/or expanded autologous Tregs and meriting further exploration.
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17 MeSH Terms
Phospho-specific flow cytometry identifies aberrant signaling in indolent B-cell lymphoma.
Blix ES, Irish JM, Husebekk A, Delabie J, Forfang L, Tierens AM, Myklebust JH, Kolstad A
(2012) BMC Cancer 12: 478
MeSH Terms: CD40 Antigens, CD40 Ligand, CD79 Antigens, Cluster Analysis, Extracellular Signal-Regulated MAP Kinases, Flow Cytometry, Humans, Interleukins, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, B-Cell, Lymphoma, B-Cell, Marginal Zone, Models, Biological, Phospholipase C gamma, Phosphoproteins, Phosphorylation, Receptors, Antigen, B-Cell, STAT5 Transcription Factor, STAT6 Transcription Factor, Signal Transduction, T-Lymphocytes, Transcription Factor RelA
Show Abstract · Added February 15, 2013
BACKGROUND - Knowledge about signaling pathways in malignant cells may provide prognostic and diagnostic information in addition to identify potential molecular targets for therapy. B-cell receptor (BCR) and co-receptor CD40 signaling is essential for normal B cells, and there is increasing evidence that signaling via BCR and CD40 plays an important role in the pathogenesis of B-cell lymphoma. The aim of this study was to investigate basal and induced signaling in lymphoma B cells and infiltrating T cells in single-cell suspensions of biopsies from small cell lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) and marginal zone lymphoma (MZL) patients.
METHODS - Samples from untreated SLL/CLL and MZL patients were examined for basal and activation induced signaling by phospho-specific flow cytometry. A panel of 9 stimulation conditions targeting B and T cells, including crosslinking of the B cell receptor (BCR), CD40 ligand and interleukins in combination with 12 matching phospho-protein readouts was used to study signaling.
RESULTS - Malignant B cells from SLL/CLL patients had higher basal levels of phosphorylated (p)-SFKs, p-PLCγ, p-ERK, p-p38, p-p65 (NF-κB), p-STAT5 and p-STAT6, compared to healthy donor B cells. In contrast, anti-BCR induced signaling was highly impaired in SLL/CLL and MZL B cells as determined by low p-SFK, p-SYK and p-PLCγ levels. Impaired anti-BCR-induced p-PLCγ was associated with reduced surface expression of IgM and CD79b. Similarly, CD40L-induced p-ERK and p-p38 were also significantly reduced in lymphoma B cells, whereas p-p65 (NF-κB) was equal to that of normal B cells. In contrast, IL-2, IL-7 and IL-15 induced p-STAT5 in tumor-infiltrating T cells were not different from normal T cells.
CONCLUSIONS - BCR signaling and CD40L-induced p-p38 was suppressed in malignant B cells from SLL/CLL and MZL patients. Single-cell phospho-specific flow cytometry for detection of basal as well as activation-induced phosphorylation of signaling proteins in distinct cell populations can be used to identify aberrant signaling pathways.
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21 MeSH Terms
FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma.
Elliott NE, Cleveland SM, Grann V, Janik J, Waldmann TA, Davé UP
(2011) Blood 118: 3911-21
MeSH Terms: Amino Acid Sequence, Animals, Cell Line, DNA Mutational Analysis, Humans, Janus Kinase 3, Leukemia-Lymphoma, Adult T-Cell, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Protein Kinase Inhibitors, Protein Structure, Tertiary, STAT5 Transcription Factor, Sequence Alignment
Show Abstract · Added March 5, 2014
Adult T-cell leukemia/lymphoma (ATLL) is an incurable disease where most patients succumb within the first year of diagnosis. Both standard chemotherapy regimens and mAbs directed against ATLL tumor markers do not alter this aggressive clinical course. Therapeutic development would be facilitated by the discovery of genes and pathways that drive or initiate ATLL, but so far amenable drug targets have not been forthcoming. Because the IL-2 signaling pathway plays a prominent role in ATLL pathogenesis, mutational analysis of pathway components should yield interesting results. In this study, we focused on JAK3, the nonreceptor tyrosine kinase that signals from the IL-2R, where activating mutations have been found in diverse neoplasms. We screened 36 ATLL patients and 24 ethnically matched controls and found 4 patients with mutations in JAK3. These somatic, missense mutations occurred in the N-terminal FERM (founding members: band 4.1, ezrin, radixin, and moesin) domain and induced gain of function in JAK3. Importantly, we show that these mutant JAK3s are inhibited with a specific kinase inhibitor already in human clinical testing. Our findings underscore the importance of this pathway in ATLL development and offer a therapeutic handle for this incurable cancer.
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14 MeSH Terms
ErbB4 splice variants Cyt1 and Cyt2 differ by 16 amino acids and exert opposing effects on the mammary epithelium in vivo.
Muraoka-Cook RS, Sandahl MA, Strunk KE, Miraglia LC, Husted C, Hunter DM, Elenius K, Chodosh LA, Earp HS
(2009) Mol Cell Biol 29: 4935-48
MeSH Terms: Alternative Splicing, Amino Acid Motifs, Amino Acids, Animals, Cell Line, Cell Nucleus, Cell Proliferation, Epithelium, ErbB Receptors, Female, Gene Expression Regulation, Humans, Mammary Glands, Animal, Mice, Milk Proteins, Phosphorylation, Pregnancy, Protein Isoforms, Protein Structure, Tertiary, Puberty, Receptor, ErbB-4, STAT5 Transcription Factor, Signal Transduction, beta Catenin
Show Abstract · Added March 5, 2014
Data concerning the prognostic value of ErbB4 in breast cancer and effects on cell growth have varied in published reports, perhaps due to the unknown signaling consequences of expression of the intracellular proteolytic ErbB4 s80(HER4) fragment or due to differing signaling capabilities of alternatively spliced ErbB4 isoforms. One isoform (Cyt1) contains a 16-residue intracellular sequence that is absent from the other (Cyt2). We expressed s80(Cyt1) and s80(Cyt2) in HC11 mammary epithelial cells, finding diametrically opposed effects on the growth and organization of colonies in three-dimensional matrices. Whereas expression of s80(Cyt1) decreased growth and increased the rate of three-dimensional lumen formation, that of s80(Cyt2) increased proliferation without promoting lumen formation. These results were recapitulated in vivo, using doxycycline-inducible, mouse breast-transgenic expression of s80(Cyt1) amd s80(Cyt2). Expression of s80(Cyt1) decreased growth of the mammary ductal epithelium, caused precocious STAT5a activation and lactogenic differentiation, and increased cell surface E-cadherin levels. Remarkably, ductal growth inhibition by s80(Cyt1) occurred simultaneously with lobuloalveolar growth that was unimpeded by s80(Cyt1), suggesting that the response to ErbB4 may be influenced by the epithelial subtype. In contrast, expression of s80(Cyt2) caused epithelial hyperplasia, increased Wnt and nuclear beta-catenin expression, and elevated expression of c-myc and cyclin D1 in the mammary epithelium. These results demonstrate that the Cyt1 and Cyt2 ErbB4 isoforms, differing by only 16 amino acids, exhibit markedly opposing effects on mammary epithelium growth and differentiation.
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24 MeSH Terms
Single-cell profiling identifies aberrant STAT5 activation in myeloid malignancies with specific clinical and biologic correlates.
Kotecha N, Flores NJ, Irish JM, Simonds EF, Sakai DS, Archambeault S, Diaz-Flores E, Coram M, Shannon KM, Nolan GP, Loh ML
(2008) Cancer Cell 14: 335-43
MeSH Terms: Adult, Biomarkers, Tumor, Cell Proliferation, Cells, Cultured, Child, Disease Progression, Flow Cytometry, Gene Expression Regulation, Neoplastic, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Janus Kinase 2, Leukemia, Myelomonocytic, Juvenile, Myeloproliferative Disorders, Neoplasm Staging, Phosphorylation, Recurrence, STAT5 Transcription Factor, Signal Transduction, Treatment Outcome
Show Abstract · Added February 15, 2013
Progress in understanding the molecular pathogenesis of human myeloproliferative disorders (MPDs) has led to guidelines incorporating genetic assays with histopathology during diagnosis. Advances in flow cytometry have made it possible to simultaneously measure cell type and signaling abnormalities arising as a consequence of genetic pathologies. Using flow cytometry, we observed a specific evoked STAT5 signaling signature in a subset of samples from patients suspected of having juvenile myelomonocytic leukemia (JMML), an aggressive MPD with a challenging clinical presentation during active disease. This signature was a specific feature involving JAK-STAT signaling, suggesting a critical role of this pathway in the biological mechanism of this disorder and indicating potential targets for future therapies.
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19 MeSH Terms
Prolactin and ErbB4/HER4 signaling interact via Janus kinase 2 to induce mammary epithelial cell gene expression differentiation.
Muraoka-Cook RS, Sandahl M, Hunter D, Miraglia L, Earp HS
(2008) Mol Endocrinol 22: 2307-21
MeSH Terms: Animals, Cell Differentiation, Cell Line, Enzyme Activation, Epithelial Cells, ErbB Receptors, Female, Gene Expression Regulation, Heparin-binding EGF-like Growth Factor, Intercellular Signaling Peptides and Proteins, Janus Kinase 2, Mammary Glands, Animal, Mice, Phosphorylation, Pregnancy, Prolactin, Receptor, ErbB-4, Receptors, Prolactin, STAT5 Transcription Factor, Signal Transduction, Tyrosine
Show Abstract · Added March 5, 2014
Differentiation of mammary epithelium in vivo requires signaling through prolactin and ErbB4/HER4-dependent mechanisms. Although stimulation of either the prolactin receptor or ErbB4/HER4 results in activation of the transcription factor signal transducer and activator of transcription 5A (STAT5A) and induction of lactogenic differentiation, how these pathways intersect is unknown. We show herein that prolactin signaling in breast cells cooperates with and is substantially enhanced by the receptor tyrosine kinase ErbB4/HER4. Prolactin and the ErbB4/HER4 ligand heparin-binding epidermal growth factor each induced STAT5A tyrosine phosphorylation and nuclear translocation; each pathway required the intracellular tyrosine kinase Janus kinase 2 (JAK2). We found that full prolactin-mediated STAT5A activation and binding to the endogenous beta-casein promoter required ErbB4/HER4 but did not require ErbB1/epidermal growth factor receptor. For example, prolactin-induced STAT5A activity was markedly diminished in cells overexpressing kinase inactive HER4, in cells transfected with small interfering RNAs to specifically knock down endogenous ErbB4/HER4 expression and in cells treated with a small molecule inhibitor that targets ErbB4 kinase. Interestingly, prolactin caused ErbB4/HER4 tyrosine phosphorylation in a JAK2 kinase-dependent manner. Finally, prolactin receptor, ErbB4/HER4, and JAK2 were coimmunoprecipitated from prolactin-treated but not untreated cells. These results suggest that prolactin signaling engages the ErbB4 pathway via JAK2 and that ErbB4 provides an important component of STAT5A-dependent lactogenic differentiation; this pathway integration may help explain the similar deficit in mammary development observed in gene-targeted mice deficient in prolactin receptor, JAK2, ErbB4, or STAT5A.
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21 MeSH Terms