MAP kinase-activating death domain protein (differentially expressed in normal & neoplastic cells, iInsulinoma-glucagonoma clone 20, Rab3 GDP/GTP exchange factor, MADD, DENN, IG20, KIAA0358)
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Function
- role in regulating cell proliferation, survival & death via alternative mRNA splicing
- isoform 5 increases cell proliferation isoform 2 decreases cell proliferation
- converts GDP-bound inactive form of RAB3A, converts RAB3C & RAB3D to GTP-bound active forms
- component of TNFRSF1A signaling complex: MADD links TNFRSF1A with MAP kinase activation
- regulatory role in physiological cell death (TNF-alpha-induced, caspase-mediated apoptosis); isoform 1 is susceptible to inducing apoptosis isoform 5 is resistant isoforms 3 & 4 have no effect
- interacts with the death domain of TNFRSF1A through its own death domain
Structure
- belongs to the MADD family
- contains 1 dDENN domain
- contains 1 death domain
- contains 1 DENN domain
- contains 1 uDENN domain
Compartment
membrane
Alternative splicing
named isoforms=7
Expression
- highly expressed in fetal brain & kidney & adult testis, ovary, brain & heart
- isoform 5 is constitutively expressed in all tissues
- isoform 7 is expressed in fetal liver
- overexpression of MADD activates one or more of the ERK family proteins
- expression of the MADD death domain stimulates both ERK & c-JUN N-terminal kinase MAP kinases & induces the phosphorylation of cytosolic phospholipase A2.
Pathology
- isoform 7 is expressed in several cancer cell lines