JNK initiates a cytokine cascade that causes Pax2 expression and closure of the optic fissure

Weston, Claire R.; Wong, Anthony; Hall, J. Perry; Goad, Mary E.P.; Davis, Roger J.

doi:10.1101/gad.1087303

Cited by 85 publications

(91 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The involvement of JNK in embryonic eyelid closure is supported by genetic evidence that the Jnk1 −/− Jnk2 +/− mice are born with open eyelids (29). Furthermore, MAP3K1 is shown haploinsufficient for eyelid closure in Jnk1 −/− and Jnk1 +/− Jnk2 +/− mice, suggesting the existence of a MAP3K1-JNK axis in eyelid development (10).…”

Section: Discussionmentioning

confidence: 53%

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) integrates developmental signals for eyelid closure

Geh¹,

Meng²,

Mongan³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Developmental eyelid closure is an evolutionarily conserved morphogenetic event requiring proliferation, differentiation, cytoskeleton reorganization, and migration of epithelial cells at the tip of the developing eyelid. Many signaling events take place during eyelid closure, but how the signals converge to regulate the morphogenetic process remains an open and intriguing question. Here we show that mitogen-activated protein kinase kinase kinase 1 (MAP3K1) highly expressed in the developing eyelid epithelium, forms with c-Jun, a regulatory axis that orchestrates morphogenesis by integrating two different networks of eyelid closure signals. A TGF-α/EGFR-RhoA module initiates one of these networks by inducing c-Jun expression which, in a phosphorylation-independent manner, binds to the Map3k1 promoter and causes an increase in MAP3K1 expression. RhoA knockout in the ocular surface epithelium disturbs this network by decreasing MAP3K1 expression, and causes delayed eyelid closure in Map3k1 hemizygotes. The second network is initiated by the enzymatic activity of MAP3K1, which phosphorylates and activates a JNK-c-Jun module, leading to AP-1 transactivation and induction of its downstream genes, such as Pai-1 . MAP3K1 inactivation reduces AP-1 activity and PAI-1 expression both in cells and developing eyelids. MAP3K1 is therefore the nexus of an intracrine regulatory loop connecting the TGF-α/EGFR/RhoA-c-Jun and JNK-c-Jun-AP-1 pathways in developmental eyelid closure.

show abstract

Section: Discussionmentioning

confidence: 53%

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) integrates developmental signals for eyelid closure

Geh¹,

Meng²,

Mongan³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…27 Depletion of JNK activity results in various epithelial defects, including those of dorsal closure and planar polarity in Drosophila, and of the optic and neuronal system in mice. [28][29][30][31][32] Since JNK is required for apoptosis and epithelial organization, disruption of the JNK signaling pathway is thought to be a prerequisite of tumorigenesis by enabling tumor cells to evade programmed cell death and to acquire a metastatic potential. 33 Indeed, JNK1 and JNK2 are both required for the suppression of oncogenic transformation and tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila

et al. 2005

View full text Add to dashboard Cite

Although recent progresses have unveiled the diverse in vivo functions of LKB1, detailed molecular mechanisms governing these processes still remain enigmatic. Here, we showed that Drosophila LKB1 negatively regulates organ growth by caspase-dependent apoptosis, without affecting cell size and cell cycle progression. Through genetic screening for LKB1 modifiers, we discovered the JNK pathway as a novel component of LKB1 signaling; the JNK pathway was activated by LKB1 and mediated the LKB1-dependent apoptosis. Consistently, LKB1-null mutant was defective in embryonic apoptosis and displayed a drastic hyperplasia in the central nervous system; these phenotypes were fully rescued by ectopic JNK activation as well as wild-type LKB1 expression. Furthermore, inhibition of LKB1 resulted in epithelial morphogenesis failure, which was associated with a decrease in JNK activity. Collectively, our studies unprecedentedly elucidate JNK as the downstream mediator of the LKB1-dependent apoptosis, and provide a new paradigm for understanding the diverse LKB1 functions in vivo.

show abstract

“…In these processes JNK is active in epithelial cells regulating their adhesive and migratory properties. There is also evidence in vertebrates for a role of JNK in several processes of epithelial morphogenesis and in wounds (42)(43)(44), which raises the possibility of a conserved module of genes exerting epithelial remodeling under the control of JNK as a ''master signal.'' The contribution of JNK to tumor progression could include the activation of MMPs and other genes driving migration and invasion in a way similar to disc eversion and closure (Fig.…”

Section: Co-option Of a Developmental Invasion Program By Tumor Cellsmentioning

confidence: 99%

Basement membrane remodeling is essential for Drosophila disc eversion and tumor invasion

Srivastava

Pastor-Pareja

Igaki

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

189

245

View full text Add to dashboard Cite

Organ and tissue integrity is often maintained in animals by a specialized extracellular matrix structure called the basement membrane (BM). Accumulated evidence indicates that BM remodeling occurs during development and tumor invasion. Although the BM organizes and functions at the organ level, most past studies have explored its biochemical and in vitro properties. In this study, we monitor the BM in vivo during developmental tissue invasion for disc eversion and tumor invasion in Drosophila and modulate BM integrity with genetic alterations affecting either the whole organism or the targeted discs or tumors. We observe that the degradation of BM by the discs or the tumors is an early event during invasion processes and that preventing BM degradation completely blocks both tissue and tumor invasion, indicating that modulation of BM is essential for developmental and tumor invasion. Furthermore, elements of the invasion machinery, including JNK-induced matrix metalloproteinase (MMP) expression, are shared by both disc eversion and tumor invasion processes. Moreover, we show that although expression of MMP inhibitor, TIMP, is sufficient to halt developmental invasion, inhibition of proteases by both TIMP and RECK are required to block tumor invasion. These data suggest that tumor cells have a more robust invasion mechanism and could acquire metastatic behavior by co-opting developmental invasion programs. This type of co-option may be a general feature contributing to the progression of tumors. Finally, although past efforts using MMP inhibitors have not yielded much success, our results strongly argue that BM modulation could be a critical target for cancer therapy.developmental invasion ͉ JNK signaling ͉ tumor metastasis ͉ matrix metalloproteinase

show abstract

JNK initiates a cytokine cascade that causes Pax2 expression and closure of the optic fissure

Cited by 85 publications

References 58 publications

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) integrates developmental signals for eyelid closure

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) integrates developmental signals for eyelid closure

JNK pathway mediates apoptotic cell death induced by tumor suppressor LKB1 in Drosophila

Basement membrane remodeling is essential for Drosophila disc eversion and tumor invasion

Contact Info

Product

Resources

About