Pathway maps

Immune response_MIF-JAB1 signaling
Immune response_MIF-JAB1 signaling

Object List (links open in MetaCore):

CDK2, N-CoR, Cyclin D1, CDK4, Ubiquitin, MIF, p27KIP1, NF-kB p50/p65, Glucocorticoids, p27KIP1, Cyclin D2, c-Jun, GRB2, UCHL1, Progesterone, JAB1, Cyclin E, Cyclin D3, Cul1/Rbx1 E3 ligase, NCOA1 (SRC1), JAB1, NF-kB1 (p50), Progesterone receptor, GCR-alpha, CRM1, JNK(MAPK8-10)

Description

MIF-JAB1 signaling

Macrophage migration inhibitory factor ( MIF ) is a pluripotent cytokine involved in inflammation and immune responses as well as in growth factor-dependent cell proliferation, cell cycle, angiogenesis, and tumorigenesis [1], [2], [3], [4].

Cells may take up MIF by endocytosis. The endocytosis can only occur when the concentration of MIF in the extracellular region is very high. Inside cells, MIF interacts with COP9 constitutive photomorphogenic homolog subunit 5 ( JAB1 ) and deactivates it. MIF antagonizes JAB1 -dependent cell-cycle regulation by stabilization of Cyclin-dependent kinase inhibitor 1B ( p27KIP1 ) and inhibits JAB1 -enhanced activity of transcription factors, such as subunit of the activator protein 1 (AP-1) Jun oncogene ( c-Jun ) [5].

JAB1 is a negative regulator of p27KIP1 by promoting its degradation via the ubiquitin/proteasome pathway mediated by Ubiquitin carboxyl-terminal esterase L1 ( UCHL1 ) and Ubiquitin Cul1/Rbx1 E3 ligase complex [6], [7], [8]. p27KIP1 binds to and prevents the activation of Cyclin E1 ( Cyclin E ) - Cyclin-dependent kinase 2 ( CDK2 ) or Cyclin D ( Cyclin D1, Cyclin D2, Cyclin D3 ) - Cyclin-dependent kinase 4 ( CDK4 ) complexes, and thus controls the cell cycle progression at G1 [9], [10], [11]. The degradation of p27KIP1, which is triggered by its CDK2 dependent phosphorylation and subsequent ubiquitination, is required for the cellular transition from quiescence to the proliferative state [12].

JAB1 is the fifth component of the COP9 signalosome complex. At least two different forms of JAB1 -containing complexes exist within the cell: one is located in the nucleus, and the other is mainly located in the cytoplasm. In the nucleus, JAB1 interacts with Exportin 1 ( CRM1 ) and functions as an adaptor between p27KIP1 and CRM1 to induce p27KIP1 nuclear export and its subsequent degradation [13]. The cytoplasmic location of p27KIP1 alone is not sufficient for induction of p27KIP1 degradation. Growth factor receptor-bound protein 2 ( GRB2 ) directly binds to p27KIP1 in the cytoplasm and is required for efficient degradation of p27KIP1 [14].

JAB1 also enhances Mitogen-activated protein kinases 8-10 ( JNK(MAPK8-10) ) activity. This increases the phosphorylation level of c-Jun, and directly potentiates the activities of several transcription factors. MIF inhibits these effects of JAB1 [5].

In the nucleus, JAB1 acts as a special regulator of c-Jun, Nuclear factor kappa-B ( NF-kB p50/p65 ) and nuclear receptors, such as Glucocorticoid receptor ( GCR-alpha ) and Progesterone receptor. JAB1 selectively potentiates c-Jun transactivation and specifically stabilizes c-Jun-containing AP-1 transcription complexes involved in inducing cell growth and proliferation [15], [5]. JAB1 also directly interacts with Progesterone receptor, GCR-alpha, and the Nuclear receptor coactivator 1 ( NCOA1 (SRC1) ). In the absence of hormone, nuclear receptors repress transcription of target genes via interactions with corepressors, such as Nuclear receptor co-repressor 1 ( N-CoR ). Upon binding of hormone, these corepressors dissociate away from the DNA-bound receptor that subsequently recruits coactivators. JAB1 stabilizes Progesterone receptor - NCOA1 (SRC1) and GCR-alpha - NCOA1 (SRC1) complexes, potentiating their transcriptional activity [16]. JAB1 also participates, at least partially, in NF-kB p50/p65 regulated casacades, through NCOA1 (SRC1) that directly interacts with NF-kB subunit p50 ( NF-kB1 (p50) ) [17], [18], [16].

References:

  1. Mitchell RA, Bucala R
    Tumor growth-promoting properties of macrophage migration inhibitory factor (MIF). Seminars in cancer biology 2000 Oct;10(5):359-66
  2. Calandra T, Froidevaux C, Martin C, Roger T
    Macrophage migration inhibitory factor and host innate immune defenses against bacterial sepsis. The Journal of infectious diseases 2003 Jun 15;187 Suppl 2:S385-90
  3. Mitchell RA
    Mechanisms and effectors of MIF-dependent promotion of tumourigenesis. Cellular signalling 2004 Jan;16(1):13-9
  4. Calandra T
    Macrophage migration inhibitory factor and host innate immune responses to microbes. Scandinavian journal of infectious diseases 2003;35(9):573-6
  5. Kleemann R, Hausser A, Geiger G, Mischke R, Burger-Kentischer A, Flieger O, Johannes FJ, Roger T, Calandra T, Kapurniotu A, Grell M, Finkelmeier D, Brunner H, Bernhagen J
    Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1. Nature 2000 Nov 9;408(6809):211-6
  6. Tomoda K, Kubota Y, Kato J
    Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature 1999 Mar 11;398(6723):160-5
  7. Caballero OL, Resto V, Patturajan M, Meerzaman D, Guo MZ, Engles J, Yochem R, Ratovitski E, Sidransky D, Jen J
    Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1). Oncogene 2002 May 2;21(19):3003-10
  8. Pray TR, Parlati F, Huang J, Wong BR, Payan DG, Bennett MK, Issakani SD, Molineaux S, Demo SD
    Cell cycle regulatory E3 ubiquitin ligases as anticancer targets. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. 2002 Dec;5(6):249-58
  9. Reynisd??ttir I, Polyak K, Iavarone A, Massagu?? J
    Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes & development 1995 Aug 1;9(15):1831-45
  10. Rivard N, L'Allemain G, Bartek J, Pouyss??gur J
    Abrogation of p27Kip1 by cDNA antisense suppresses quiescence (G0 state) in fibroblasts. The Journal of biological chemistry 1996 Aug 2;271(31):18337-41
  11. Vidal A, Koff A
    Cell-cycle inhibitors: three families united by a common cause. Gene 2000 Apr 18;247(1-2):1-15
  12. Montagnoli A, Fiore F, Eytan E, Carrano AC, Draetta GF, Hershko A, Pagano M
    Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation. Genes & development 1999 May 1;13(9):1181-9
  13. Tomoda K, Kubota Y, Arata Y, Mori S, Maeda M, Tanaka T, Yoshida M, Yoneda-Kato N, Kato JY
    The cytoplasmic shuttling and subsequent degradation of p27Kip1 mediated by Jab1/CSN5 and the COP9 signalosome complex. The Journal of biological chemistry 2002 Jan 18;277(3):2302-10
  14. Sugiyama Y, Tomoda K, Tanaka T, Arata Y, Yoneda-Kato N, Kato J
    Direct binding of the signal-transducing adaptor Grb2 facilitates down-regulation of the cyclin-dependent kinase inhibitor p27Kip1. The Journal of biological chemistry 2001 Apr 13;276(15):12084-90
  15. Claret FX, Hibi M, Dhut S, Toda T, Karin M
    A new group of conserved coactivators that increase the specificity of AP-1 transcription factors. Nature 1996 Oct 3;383(6599):453-7
  16. Chauchereau A, Georgiakaki M, Perrin-Wolff M, Milgrom E, Loosfelt H
    JAB1 interacts with both the progesterone receptor and SRC-1. The Journal of biological chemistry 2000 Mar 24;275(12):8540-8
  17. Na SY, Lee SK, Han SJ, Choi HS, Im SY, Lee JW
    Steroid receptor coactivator-1 interacts with the p50 subunit and coactivates nuclear factor kappaB-mediated transactivations. The Journal of biological chemistry 1998 May 1;273(18):10831-4
  18. Leo C, Chen JD
    The SRC family of nuclear receptor coactivators. Gene 2000 Mar 7;245(1):1-11