![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Vol. 14, Issue 4, 1448-1459, April 2003
§ and
¶
*Haartman Institute, Department of Virology and
Jak tyrosine kinases have a unique domain structure containing a
kinase domain (JH1) adjacent to a catalytically inactive pseudokinase
domain (JH2). JH2 is crucial for inhibition of basal Jak activity, but
the mechanism of this regulation has remained elusive. We show that JH2
negatively regulated Jak2 in bacterial cells, indicating that
regulation is an intrinsic property of Jak2. JH2 suppressed basal Jak2
activity by lowering the Vmax of Jak2,
whereas JH2 did not affect the Km of Jak2
for a peptide substrate. Three inhibitory regions (IR1-3) within JH2
were identified. IR3 (residues 758-807), at the C terminus of JH2,
directly inhibited JH1, suggesting an inhibitory interaction between
IR3 and JH1. Molecular modeling of JH2 showed that IR3 could form a
stable Biomedicum Helsinki, Programme for Developmental
and Reproductive Biology, University of Helsinki, Helsinki FIN-00014,
Finland; Institute for Medical Technology,
University of Tampere, Tampere FIN-33014, Finland;
§Research Unit, Tampere University Hospital,
Tampere FIN-33101, Finland; and Department of
Clinical Microbiology, Tampere University Hospital, FIN-33101 Tampere,
Finland
-helical fold, supporting that IR3 could independently
inhibit JH1. IR2 (725-757) in the C-terminal lobe of JH2, and IR1
(619-670), extending from the N-terminal to the C-terminal lobe,
enhanced IR3-mediated inhibition of JH1. Disruption of IR3 either by
mutations or a small deletion increased basal Jak2 activity, but
abolished interferon-
-inducible signaling. Together, the
results provide evidence for autoinhibition of a Jak family kinase and
identify JH2 regions important for autoregulation of Jak2.
This article has been cited by other articles:
|
|
 |
|
  M. Kurdi and G. W. Booz JAK redux: a second look at the regulation and role of JAKs in the heart Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1545 - H1556. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Zhao, H. Dong, C. C. Zhang, L. Kinch, M. Osawa, M. Iacovino, N. V. Grishin, M. Kyba, and L. J.-s. Huang A JAK2 Interdomain Linker Relays Epo Receptor Engagement Signals to Kinase Activation J. Biol. Chem., September 25, 2009; 284(39): 26988 - 26998. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Funakoshi-Tago, K. Tago, K. Sumi, M. Abe, E. Aizu-Yokota, T. Oshio, Y. Sonoda, and T. Kasahara The Acute Lymphoblastic Leukemia-associated JAK2 L611S Mutant Induces Tumorigenesis in Nude Mice J. Biol. Chem., May 8, 2009; 284(19): 12680 - 12690. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kaushansky Determinants of platelet number and regulation of thrombopoiesis Hematology, January 1, 2009; 2009(1): 147 - 152. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Manning, S. L. Young, W. T. Miller, and Y. Zhai From the Cover: The protist, Monosiga brevicollis, has a tyrosine kinase signaling network more elaborate and diverse than found in any known metazoan PNAS, July 15, 2008; 105(28): 9674 - 9679. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Cheng, J. A. Ross, J. A. Frost, and R. A. Kirken Phosphorylation of Human Jak3 at Tyrosines 904 and 939 Positively Regulates Its Activity Mol. Cell. Biol., April 1, 2008; 28(7): 2271 - 2282. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Funakoshi-Tago, S. Pelletier, H. Moritake, E. Parganas, and J. N. Ihle Jak2 FERM Domain Interaction with the Erythropoietin Receptor Regulates Jak2 Kinase Activity Mol. Cell. Biol., March 1, 2008; 28(5): 1792 - 1801. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Skoda The Genetic Basis of Myeloproliferative Disorders Hematology, January 1, 2007; 2007(1): 1 - 10. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Kurzer, P. Saharinen, O. Silvennoinen, and C. Carter-Su Binding of SH2-B Family Members within a Potential Negative Regulatory Region Maintains JAK2 in an Active State Mol. Cell. Biol., September 1, 2006; 26(17): 6381 - 6394. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Walz, B. J. Crowley, H. E. Hudon, J. L. Gramlich, D. S. Neuberg, K. Podar, J. D. Griffin, and M. Sattler Activated Jak2 with the V617F Point Mutation Promotes G1/S Phase Transition J. Biol. Chem., June 30, 2006; 281(26): 18177 - 18183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Mazurkiewicz-Munoz, L. S. Argetsinger, J.-L. K. Kouadio, A. Stensballe, O. N. Jensen, J. M. Cline, and C. Carter-Su Phosphorylation of JAK2 at Serine 523: a Negative Regulator of JAK2 That Is Stimulated by Growth Hormone and Epidermal Growth Factor Mol. Cell. Biol., June 1, 2006; 26(11): 4052 - 4062. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. I. Schafer Molecular basis of the diagnosis and treatment of polycythemia vera and essential thrombocythemia Blood, June 1, 2006; 107(11): 4214 - 4222. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. S. Lucet, E. Fantino, M. Styles, R. Bamert, O. Patel, S. E. Broughton, M. Walter, C. J. Burns, H. Treutlein, A. F. Wilks, et al. The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor Blood, January 1, 2006; 107(1): 176 - 183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. V. Jones, S. Kreil, K. Zoi, K. Waghorn, C. Curtis, L. Zhang, J. Score, R. Seear, A. J. Chase, F. H. Grand, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders Blood, September 15, 2005; 106(6): 2162 - 2168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Zhao, S. Xing, Z. Li, X. Fu, Q. Li, S. B. Krantz, and Z. J. Zhao Identification of an Acquired JAK2 Mutation in Polycythemia Vera J. Biol. Chem., June 17, 2005; 280(24): 22788 - 22792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kaushansky On the molecular origins of the chronic myeloproliferative disorders: it all makes sense Blood, June 1, 2005; 105(11): 4187 - 4190. [Full Text] [PDF]
|
|
|
|
 |
|
 R. Kralovics, F. Passamonti, A. S. Buser, S.-S. Teo, R. Tiedt, J. R. Passweg, A. Tichelli, M. Cazzola, and R. C. Skoda A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders N. Engl. J. Med., April 28, 2005; 352(17): 1779 - 1790. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Novotny-Diermayr, B. Lin, L. Gu, and X. Cao Modulation of the Interleukin-6 Receptor Subunit Glycoprotein 130 Complex and Its Signaling by LMO4 Interaction J. Biol. Chem., April 1, 2005; 280(13): 12747 - 12757. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Boudeau, J. W. Scott, N. Resta, M. Deak, A. Kieloch, D. Komander, D. G. Hardie, A. R. Prescott, D. M. F. van Aalten, and D. R. Alessi Analysis of the LKB1-STRAD-MO25 complex J. Cell Sci., December 15, 2004; 117(26): 6365 - 6375. [Abstract] [Full Text] [PDF]
|
|
