| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Activates the C3G/Rap1 Signaling Pathway1
*
Section of Hematology-Oncology, University of Illinois at Chicago and West Side Veterans Affairs Medical Center, Chicago, IL 60607;
Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario, Canada; and
Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland, OR 97201
IFN-
transduces signals by activating the IFN-
receptor-associated Jak-1 and Jak-2 kinases and by inducing tyrosine
phosphorylation and activation of the Stat-1 transcriptional activator.
We report that IFN- activates a distinct signaling cascade involving
the c-cbl protooncogene product, CrkL adapter, and small
G protein Rap1. During treatment of NB-4 human cells with IFN-,
c-cbl protooncogene product is rapidly phosphorylated on
tyrosine and provides a docking site for the src homology 2 domain of
CrkL, which also undergoes IFN--dependent tyrosine phosphorylation.
CrkL then regulates activation of the guanine exchange factor C3G, with
which it interacts constitutively via its N terminus src homology 3
domain. This results in the IFN--dependent activation of Rap1, a
protein known to exhibit tumor suppressor activity and mediate growth
inhibitory responses. In a similar manner, Rap1 is also activated in
response to treatment of cells with type I IFNs (IFN-
, IFN-ß),
which also engage CrkL in their signaling pathways. On the other hand,
IFN- does not induce formation of nuclear CrkL-Stat5 DNA-binding
complexes, which are induced by IFN- and IFN-ß, indicating that
pathways downstream of CrkL are differentially regulated by different
IFN subtypes. Taken altogether, our data demonstrate that, in addition
to activating the Stat pathway, IFN- activates a distinct signaling
cascade that may play an important role in the generation of its growth
inhibitory effects on target cells.
This article has been cited by other articles:
|
|
 |
|
  Y. Bai, U. Ahmad, Y. Wang, J. H. Li, J. C. Choy, R. W. Kim, N. Kirkiles-Smith, S. E. Maher, J. G. Karras, C. F. Bennett, et al. Interferon-{gamma} Induces X-linked Inhibitor of Apoptosis-associated Factor-1 and Noxa Expression and Potentiates Human Vascular Smooth Muscle Cell Apoptosis by STAT3 Activation J. Biol. Chem., March 14, 2008; 283(11): 6832 - 6842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Gough, K. Sabapathy, E. Y.-N. Ko, H. A. Arthur, R. D. Schreiber, J. A. Trapani, C. J. P. Clarke, and R. W. Johnstone A Novel c-Jun-dependent Signal Transduction Pathway Necessary for the Transcriptional Activation of Interferon {gamma} Response Genes J. Biol. Chem., January 12, 2007; 282(2): 938 - 946. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. S. Stork and T. J. Dillon Multiple roles of Rap1 in hematopoietic cells: complementary versus antagonistic functions Blood, November 1, 2005; 106(9): 2952 - 2961. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Pawliczak, C. Logun, P. Madara, J. Barb, A. F. Suffredini, P. J. Munson, R. L. Danner, and J. H. Shelhamer Influence of IFN-{gamma} on gene expression in normal human bronchial epithelial cells: modulation of IFN-{gamma} effects by dexamethasone Physiol Genomics, September 21, 2005; 23(1): 28 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, S. Batra, A. Sassano, B. Majchrzak, D. E. Levy, M. Gaestel, E. N. Fish, R. J. Davis, and L. C. Platanias Activation of Mitogen-activated Protein Kinase Kinase (MKK) 3 and MKK6 by Type I Interferons J. Biol. Chem., March 18, 2005; 280(11): 10001 - 10010. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Srivastava, S. Batra, A. Sassano, Y. Li, B. Majchrzak, H. Kiyokawa, A. Altman, E. N. Fish, and L. C. Platanias Engagement of Protein Kinase C-{theta} in Interferon Signaling in T-cells J. Biol. Chem., July 16, 2004; 279(29): 29911 - 29920. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, A. Sassano, B. Majchrzak, D. K. Deb, D. E. Levy, M. Gaestel, A. R. Nebreda, E. N. Fish, and L. C. Platanias Role of p38{alpha} Map Kinase in Type I Interferon Signaling J. Biol. Chem., January 9, 2004; 279(2): 970 - 979. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. K. Deb, A. Sassano, F. Lekmine, B. Majchrzak, A. Verma, S. Kambhampati, S. Uddin, A. Rahman, E. N. Fish, and L. C. Platanias Activation of Protein Kinase C{delta} by IFN-{gamma} J. Immunol., July 1, 2003; 171(1): 267 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Navarro, B. Anand-Apte, Y. Tanabe, G. Feldman, and A. C. Larner A PI-3 kinase-dependent, Stat1-independent signaling pathway regulates interferon-stimulated monocyte adhesion J. Leukoc. Biol., April 1, 2003; 73(4): 540 - 545. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. Voss, P. Gruss, and T. Thomas The guanine nucleotide exchange factor C3G is necessary for the formation of focal adhesions and vascular maturation Development, March 2, 2003; 130(2): 355 - 367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Uddin, A. Sassano, D. K. Deb, A. Verma, B. Majchrzak, A. Rahman, A. B. Malik, E. N. Fish, and L. C. Platanias Protein Kinase C-delta (PKC-delta ) Is Activated by Type I Interferons and Mediates Phosphorylation of Stat1 on Serine 727 J. Biol. Chem., April 19, 2002; 277(17): 14408 - 14416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Verma, D. K. Deb, A. Sassano, S. Uddin, J. Varga, A. Wickrema, and L. C. Platanias Activation of the p38 Mitogen-activated Protein Kinase Mediates the Suppressive Effects of Type I Interferons and Transforming Growth Factor-beta on Normal Hematopoiesis J. Biol. Chem., March 1, 2002; 277(10): 7726 - 7735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Du, Y. M. Alsayed, F. Xin, S. J. Ackerman, and L. C. Platanias Engagement of the CrkL Adapter in Interleukin-5 Signaling in Eosinophils J. Biol. Chem., October 13, 2000; 275(42): 33167 - 33175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Arai, Y. Nosaka, E. Kanda, K. Yamamoto, N. Miyasaka, and O. Miura Rap1 Is Activated by Erythropoietin or Interleukin-3 and Is Involved in Regulation of beta 1 Integrin-mediated Hematopoietic Cell Adhesion J. Biol. Chem., March 23, 2001; 276(13): 10453 - 10462. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
