APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl

T. Wakioka, A. Sasaki, K. Mitsui, M. Yokouchi, A. Inoue, S. Komiya, Akihiko Yoshimura

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

We cloned a novel adaptor protein, APS (adaptor molecule containing Pleckstrin homology (PH) and Src Homology-2 (SH2) domains), which was tyrosine phosphorylated in response to c-kit or B cell receptor stimulation. Here, we report that APS was tyrosine phosphorylated by Janus kinase-2 (JAK2) at its C-terminal tyrosine residue and interacted with c-Cbl. Forced expression of APS in an erythropoietin (EPO)-dependent hematopoietic cell line resulted in reduced activation of STAT5 but not cell proliferation in response to EPO. APS bound to the phosphorylated tyrosine residue, Y343 of the erythropoietin receptor cytoplasmic domain. Co-expression of APS and c-Cbl, but not expression of either alone inhibited EPO-dependent STAT5 activation in 293 cells. This required the C-terminal phosphorylation site, as well as PH and SH2 domains of APS. Therefore, one of the major functions of APS is in recruitment of c-Cbl into the receptor/JAK complex, thereby inhibiting JAK signaling activity.

Original languageEnglish
Pages (from-to)760-767
Number of pages8
JournalLeukemia
Volume13
Issue number5
Publication statusPublished - 1999
Externally publishedYes

Fingerprint

src Homology Domains
Tyrosine
Erythropoietin
Proteins
Janus Kinase 2
Erythropoietin Receptors
B-Lymphocytes
Phosphorylation
Cell Proliferation
Cell Line
platelet protein P47

Keywords

  • APS
  • c-Cbl
  • Cytokine
  • JAK
  • Signal transduction
  • STAT

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

Cite this

APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl. / Wakioka, T.; Sasaki, A.; Mitsui, K.; Yokouchi, M.; Inoue, A.; Komiya, S.; Yoshimura, Akihiko.

In: Leukemia, Vol. 13, No. 5, 1999, p. 760-767.

Research output: Contribution to journalArticle

Wakioka, T. ; Sasaki, A. ; Mitsui, K. ; Yokouchi, M. ; Inoue, A. ; Komiya, S. ; Yoshimura, Akihiko. / APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl. In: Leukemia. 1999 ; Vol. 13, No. 5. pp. 760-767.
@article{2d7bfd69ed7e495ca0aec9c067e44f02,
title = "APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl",
abstract = "We cloned a novel adaptor protein, APS (adaptor molecule containing Pleckstrin homology (PH) and Src Homology-2 (SH2) domains), which was tyrosine phosphorylated in response to c-kit or B cell receptor stimulation. Here, we report that APS was tyrosine phosphorylated by Janus kinase-2 (JAK2) at its C-terminal tyrosine residue and interacted with c-Cbl. Forced expression of APS in an erythropoietin (EPO)-dependent hematopoietic cell line resulted in reduced activation of STAT5 but not cell proliferation in response to EPO. APS bound to the phosphorylated tyrosine residue, Y343 of the erythropoietin receptor cytoplasmic domain. Co-expression of APS and c-Cbl, but not expression of either alone inhibited EPO-dependent STAT5 activation in 293 cells. This required the C-terminal phosphorylation site, as well as PH and SH2 domains of APS. Therefore, one of the major functions of APS is in recruitment of c-Cbl into the receptor/JAK complex, thereby inhibiting JAK signaling activity.",
keywords = "APS, c-Cbl, Cytokine, JAK, Signal transduction, STAT",
author = "T. Wakioka and A. Sasaki and K. Mitsui and M. Yokouchi and A. Inoue and S. Komiya and Akihiko Yoshimura",
year = "1999",
language = "English",
volume = "13",
pages = "760--767",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl

AU - Wakioka, T.

AU - Sasaki, A.

AU - Mitsui, K.

AU - Yokouchi, M.

AU - Inoue, A.

AU - Komiya, S.

AU - Yoshimura, Akihiko

PY - 1999

Y1 - 1999

N2 - We cloned a novel adaptor protein, APS (adaptor molecule containing Pleckstrin homology (PH) and Src Homology-2 (SH2) domains), which was tyrosine phosphorylated in response to c-kit or B cell receptor stimulation. Here, we report that APS was tyrosine phosphorylated by Janus kinase-2 (JAK2) at its C-terminal tyrosine residue and interacted with c-Cbl. Forced expression of APS in an erythropoietin (EPO)-dependent hematopoietic cell line resulted in reduced activation of STAT5 but not cell proliferation in response to EPO. APS bound to the phosphorylated tyrosine residue, Y343 of the erythropoietin receptor cytoplasmic domain. Co-expression of APS and c-Cbl, but not expression of either alone inhibited EPO-dependent STAT5 activation in 293 cells. This required the C-terminal phosphorylation site, as well as PH and SH2 domains of APS. Therefore, one of the major functions of APS is in recruitment of c-Cbl into the receptor/JAK complex, thereby inhibiting JAK signaling activity.

AB - We cloned a novel adaptor protein, APS (adaptor molecule containing Pleckstrin homology (PH) and Src Homology-2 (SH2) domains), which was tyrosine phosphorylated in response to c-kit or B cell receptor stimulation. Here, we report that APS was tyrosine phosphorylated by Janus kinase-2 (JAK2) at its C-terminal tyrosine residue and interacted with c-Cbl. Forced expression of APS in an erythropoietin (EPO)-dependent hematopoietic cell line resulted in reduced activation of STAT5 but not cell proliferation in response to EPO. APS bound to the phosphorylated tyrosine residue, Y343 of the erythropoietin receptor cytoplasmic domain. Co-expression of APS and c-Cbl, but not expression of either alone inhibited EPO-dependent STAT5 activation in 293 cells. This required the C-terminal phosphorylation site, as well as PH and SH2 domains of APS. Therefore, one of the major functions of APS is in recruitment of c-Cbl into the receptor/JAK complex, thereby inhibiting JAK signaling activity.

KW - APS

KW - c-Cbl

KW - Cytokine

KW - JAK

KW - Signal transduction

KW - STAT

UR - http://www.scopus.com/inward/record.url?scp=0033056041&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033056041&partnerID=8YFLogxK

M3 - Article

VL - 13

SP - 760

EP - 767

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 5

ER -