Coactivation of Janus tyrosine kinase (Jak)1 positively modulates prolactin-Jak2 signaling in breast cancer

Recruitment of ERK and signal transducer and activator of transcription (Stat)3 and enhancement of Akt and Stat5a/b pathways

Lynn M. Neilson, Jianquong Zhu, Jianwu Xie, M. Grazia Malabarba, Kazuhito Sakamoto, Kay-Uwe Wagner, Robert A. Kirken, Hallgeir Rui

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Prolactin (PRL) receptors (PRLRs) have been considered selective activators of Janus tyrosine kinase (Jak)2 but not Jak1, Jak3, or Tyk2. We now report marked PRL-induced tyrosine phosphorylation of Jak1, in addition to Jak2, in a series of human breast cancer cell lines, including T47D, MCF7, and SKBR3. In contrast, PRL did not activate Jak1 in immortalized, noncancerous breast epithelial lines HC11, MCF10A, ME16C, and HBL-100, or in CWR22Rv1 prostate cancer cells or MDA-MB-231 breast cancer cells. However, introduction of exogenous PRLR into MCF10A, ME16C, or MDA-MB-231 cells reconstituted both PRL-Jak1 and PRL-Jak2 signals. In vitro kinase assays verified that PRL stimulated enzymatic activity of Jak1 in T47D cells, and PRL activated Jak1 and Jak2 with indistinguishable time and dose kinetics. Relative Jak2 deficiency did not cause PRLR activation of Jak1, because overexpression of Jak2 did not interfere with PRL activation of Jak1. Instead, PRL activated Jak1 through a Jak2-dependent mechanism, based on disruption of PRL activation of Jak1 after Jak2 suppression by 1) lentiviral delivery of Jak2 short hairpin RNA, 2) adenoviral delivery of dominant-negative Jak2, and 3) AG490 pharmacological inhibition. Finally, suppression of Jak1 by lentiviral delivery of Jak1 short hairpin RNA blocked PRL activation of ERK and signal transducer and activator of transcription (Stat)3 and suppressed PRL activation of Jak2, Stat5a, Stat5b, and Akt, as well as tyrosine phosphorylation of PRLR. The data suggest that PRL activation of Jak1 represents a novel, Jak2-dependent mechanism that may serve as a regulatory switch leading to PRL activation of ERK and Stat3 pathways, while also serving to enhance PRL-induced Stat5a/b and Akt signaling.

Original languageEnglish (US)
Pages (from-to)2218-2232
Number of pages15
JournalMolecular Endocrinology
Volume21
Issue number9
DOIs
StatePublished - Sep 1 2007

Fingerprint

Janus Kinase 1
STAT3 Transcription Factor
Prolactin
Protein-Tyrosine Kinases
Breast Neoplasms
Prolactin Receptors
Small Interfering RNA
Tyrosine
TYK2 Kinase
Phosphorylation
Janus Kinase 2
MAP Kinase Signaling System

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Coactivation of Janus tyrosine kinase (Jak)1 positively modulates prolactin-Jak2 signaling in breast cancer : Recruitment of ERK and signal transducer and activator of transcription (Stat)3 and enhancement of Akt and Stat5a/b pathways. / Neilson, Lynn M.; Zhu, Jianquong; Xie, Jianwu; Malabarba, M. Grazia; Sakamoto, Kazuhito; Wagner, Kay-Uwe; Kirken, Robert A.; Rui, Hallgeir.

In: Molecular Endocrinology, Vol. 21, No. 9, 01.09.2007, p. 2218-2232.

Research output: Contribution to journalArticle

Neilson, Lynn M. ; Zhu, Jianquong ; Xie, Jianwu ; Malabarba, M. Grazia ; Sakamoto, Kazuhito ; Wagner, Kay-Uwe ; Kirken, Robert A. ; Rui, Hallgeir. / Coactivation of Janus tyrosine kinase (Jak)1 positively modulates prolactin-Jak2 signaling in breast cancer : Recruitment of ERK and signal transducer and activator of transcription (Stat)3 and enhancement of Akt and Stat5a/b pathways. In: Molecular Endocrinology. 2007 ; Vol. 21, No. 9. pp. 2218-2232.
@article{67d35d4f4fd7490eb7cee79a6fe96cf3,
title = "Coactivation of Janus tyrosine kinase (Jak)1 positively modulates prolactin-Jak2 signaling in breast cancer: Recruitment of ERK and signal transducer and activator of transcription (Stat)3 and enhancement of Akt and Stat5a/b pathways",
abstract = "Prolactin (PRL) receptors (PRLRs) have been considered selective activators of Janus tyrosine kinase (Jak)2 but not Jak1, Jak3, or Tyk2. We now report marked PRL-induced tyrosine phosphorylation of Jak1, in addition to Jak2, in a series of human breast cancer cell lines, including T47D, MCF7, and SKBR3. In contrast, PRL did not activate Jak1 in immortalized, noncancerous breast epithelial lines HC11, MCF10A, ME16C, and HBL-100, or in CWR22Rv1 prostate cancer cells or MDA-MB-231 breast cancer cells. However, introduction of exogenous PRLR into MCF10A, ME16C, or MDA-MB-231 cells reconstituted both PRL-Jak1 and PRL-Jak2 signals. In vitro kinase assays verified that PRL stimulated enzymatic activity of Jak1 in T47D cells, and PRL activated Jak1 and Jak2 with indistinguishable time and dose kinetics. Relative Jak2 deficiency did not cause PRLR activation of Jak1, because overexpression of Jak2 did not interfere with PRL activation of Jak1. Instead, PRL activated Jak1 through a Jak2-dependent mechanism, based on disruption of PRL activation of Jak1 after Jak2 suppression by 1) lentiviral delivery of Jak2 short hairpin RNA, 2) adenoviral delivery of dominant-negative Jak2, and 3) AG490 pharmacological inhibition. Finally, suppression of Jak1 by lentiviral delivery of Jak1 short hairpin RNA blocked PRL activation of ERK and signal transducer and activator of transcription (Stat)3 and suppressed PRL activation of Jak2, Stat5a, Stat5b, and Akt, as well as tyrosine phosphorylation of PRLR. The data suggest that PRL activation of Jak1 represents a novel, Jak2-dependent mechanism that may serve as a regulatory switch leading to PRL activation of ERK and Stat3 pathways, while also serving to enhance PRL-induced Stat5a/b and Akt signaling.",
author = "Neilson, {Lynn M.} and Jianquong Zhu and Jianwu Xie and Malabarba, {M. Grazia} and Kazuhito Sakamoto and Kay-Uwe Wagner and Kirken, {Robert A.} and Hallgeir Rui",
year = "2007",
month = "9",
day = "1",
doi = "10.1210/me.2007-0173",
language = "English (US)",
volume = "21",
pages = "2218--2232",
journal = "Molecular Endocrinology",
issn = "0888-8809",
publisher = "The Endocrine Society",
number = "9",

}

TY - JOUR

T1 - Coactivation of Janus tyrosine kinase (Jak)1 positively modulates prolactin-Jak2 signaling in breast cancer

T2 - Recruitment of ERK and signal transducer and activator of transcription (Stat)3 and enhancement of Akt and Stat5a/b pathways

AU - Neilson, Lynn M.

AU - Zhu, Jianquong

AU - Xie, Jianwu

AU - Malabarba, M. Grazia

AU - Sakamoto, Kazuhito

AU - Wagner, Kay-Uwe

AU - Kirken, Robert A.

AU - Rui, Hallgeir

PY - 2007/9/1

Y1 - 2007/9/1

N2 - Prolactin (PRL) receptors (PRLRs) have been considered selective activators of Janus tyrosine kinase (Jak)2 but not Jak1, Jak3, or Tyk2. We now report marked PRL-induced tyrosine phosphorylation of Jak1, in addition to Jak2, in a series of human breast cancer cell lines, including T47D, MCF7, and SKBR3. In contrast, PRL did not activate Jak1 in immortalized, noncancerous breast epithelial lines HC11, MCF10A, ME16C, and HBL-100, or in CWR22Rv1 prostate cancer cells or MDA-MB-231 breast cancer cells. However, introduction of exogenous PRLR into MCF10A, ME16C, or MDA-MB-231 cells reconstituted both PRL-Jak1 and PRL-Jak2 signals. In vitro kinase assays verified that PRL stimulated enzymatic activity of Jak1 in T47D cells, and PRL activated Jak1 and Jak2 with indistinguishable time and dose kinetics. Relative Jak2 deficiency did not cause PRLR activation of Jak1, because overexpression of Jak2 did not interfere with PRL activation of Jak1. Instead, PRL activated Jak1 through a Jak2-dependent mechanism, based on disruption of PRL activation of Jak1 after Jak2 suppression by 1) lentiviral delivery of Jak2 short hairpin RNA, 2) adenoviral delivery of dominant-negative Jak2, and 3) AG490 pharmacological inhibition. Finally, suppression of Jak1 by lentiviral delivery of Jak1 short hairpin RNA blocked PRL activation of ERK and signal transducer and activator of transcription (Stat)3 and suppressed PRL activation of Jak2, Stat5a, Stat5b, and Akt, as well as tyrosine phosphorylation of PRLR. The data suggest that PRL activation of Jak1 represents a novel, Jak2-dependent mechanism that may serve as a regulatory switch leading to PRL activation of ERK and Stat3 pathways, while also serving to enhance PRL-induced Stat5a/b and Akt signaling.

AB - Prolactin (PRL) receptors (PRLRs) have been considered selective activators of Janus tyrosine kinase (Jak)2 but not Jak1, Jak3, or Tyk2. We now report marked PRL-induced tyrosine phosphorylation of Jak1, in addition to Jak2, in a series of human breast cancer cell lines, including T47D, MCF7, and SKBR3. In contrast, PRL did not activate Jak1 in immortalized, noncancerous breast epithelial lines HC11, MCF10A, ME16C, and HBL-100, or in CWR22Rv1 prostate cancer cells or MDA-MB-231 breast cancer cells. However, introduction of exogenous PRLR into MCF10A, ME16C, or MDA-MB-231 cells reconstituted both PRL-Jak1 and PRL-Jak2 signals. In vitro kinase assays verified that PRL stimulated enzymatic activity of Jak1 in T47D cells, and PRL activated Jak1 and Jak2 with indistinguishable time and dose kinetics. Relative Jak2 deficiency did not cause PRLR activation of Jak1, because overexpression of Jak2 did not interfere with PRL activation of Jak1. Instead, PRL activated Jak1 through a Jak2-dependent mechanism, based on disruption of PRL activation of Jak1 after Jak2 suppression by 1) lentiviral delivery of Jak2 short hairpin RNA, 2) adenoviral delivery of dominant-negative Jak2, and 3) AG490 pharmacological inhibition. Finally, suppression of Jak1 by lentiviral delivery of Jak1 short hairpin RNA blocked PRL activation of ERK and signal transducer and activator of transcription (Stat)3 and suppressed PRL activation of Jak2, Stat5a, Stat5b, and Akt, as well as tyrosine phosphorylation of PRLR. The data suggest that PRL activation of Jak1 represents a novel, Jak2-dependent mechanism that may serve as a regulatory switch leading to PRL activation of ERK and Stat3 pathways, while also serving to enhance PRL-induced Stat5a/b and Akt signaling.

UR - http://www.scopus.com/inward/record.url?scp=34548348216&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34548348216&partnerID=8YFLogxK

U2 - 10.1210/me.2007-0173

DO - 10.1210/me.2007-0173

M3 - Article

VL - 21

SP - 2218

EP - 2232

JO - Molecular Endocrinology

JF - Molecular Endocrinology

SN - 0888-8809

IS - 9

ER -