ORGANELLE MARKERS - Plasma membrane

CD40

CD40 is a 45-50 kDa type I membrane protein and a member of the tumor necrosis factor (TNF) receptor superfamily. CD40 is also known as pb50 or CDW40. CD40 is expressed primarily by professional antigen-presenting cells and it is also expressed on nonimmune cell types. The CD40 expressed by professional antigen-presenting cells plays a critical role in costimulation and antigen-presenting cell activation in T cell-dependant immune responses. Signals generated through CD40 in B cells are antiapoptotic. These signals are also required for T cell-dependant B cell activation and proliferation, isotype switching, up-regulation of costimulatory receptors, germinal center formation and memory generation. CD40 signal transduction is initiated by binding trimeric CD40 ligand (CD40L) which is found on the surface of activated T cells. CD40 engages several signalling pathways in B cells and these include NF-kappaB, the mitogen-activated protein kinases p38 and c-Jun N-terminal kinase. The 62 amino acid cytoplasmic domain (CD40c) of CD40 contains two linear TNF-receptor associated factor (TRAF) binding domains. The membrane proximal site of CD40c binds TRAF6 and the membrane distal site binds TRAF1, 2 and 3. CD40c is thought to mediate the CD40-dependant signaling pathways by recruitment of TRAF to this multimerized domain . CD40 ligation has also been shown to stimulate iNOS expression, and therefore NO production, by activating NF-kappaB in IFN-?treated microglial cells . NO derived from microglia has been implicated in the damage of myelin-producing oligodendrocytes in demyelating disorders like multiple sclerosis (MS) and neuronal death during Alzheimer.s disease and brain trauma. Increased CD40-CD40 ligation has beenimplicated in the pathogenesis of several autoimmune inflammatory diseases, such as MS, arthritis and insulin-dependant diabetes.

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CD40 Ligand

CD40 ligand (CD40L), also known as CD154, gp39 and TRAP, is a 33 kDa type II membrane glycoprotein expressed mainly on the cell surface of activated T lymphocytes but also exists as a soluble form extracellularly. CD40L is the ligand for CD40, a member of the TNF superfamily, which is expressed on the cell surface of B cells, macrophages/monocytes, dendritic cells, vascular endothelial cells, and epithelial cells. CD40L plays an important role in B cell proliferation, antibody class switching, modulation of apoptosis in the germinal center through interaction with B cells expressing CD40, and activation of CD4+ T cells. Mutation within the CD40L gene is linked to hyper IgM syndrome, an Xlinked immunodeficiency disease that is characterized by elevated level of serum IgM and decreased level of other isotypes.

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Fas/APO-1

Fas/APO-1/CD95 is a 36 kDa cell surface type I-membrane glycoprotein with an apparent molecular weight of 44 kDa on SDSPAGE. Fas is a member of the tumor necrosis factor receptor (TNFR) family, which includes TNFR1, TNFR2, CD27, CD30 and CD40. Binding of Fas-ligand (FasL) to Fas or crosslinking of Fas by anti-Fas monoclonal antibodies leads to apoptosis of Fas expressing cells. Both Fas and TNFR contain a 70 amino acids cytoplasmic .death domain. that is responsible for transmitting signal for apoptosis. Apoptosis induced by Fas-Fas ligand interaction is inhibited by a number of cytosolic factors such as the ICE/CED3 family inhibitor CrmA, and the short and long form of FLIP. Insertion of an early transposable element in intron 2 of Fas structural gene, as in the mouse lpr mutations, causes lymphoproliferation and autoimmunity in mutant mice, suggesting that Fas is involved in clonal deletion of autoreactive T cells.

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Tumor Necrosis Factor Receptor 1 & 2

Tumor necrosis factor receptor 1 and 2 (TNF-R1 and TNF-R2), are 55 and 75 kDa members of a family cell surface molecules including nerve growth factor receptor, Fas/Apo-1, CD30, Ox40 and 4-1BB, which are characterized by cysteine rich motifs in the extracellular domain. While TNF-R1 and TNF-R2 share 28% sequence identity in their extracellular domains, their intracellular domains lack sequence homology which suggests that they differ in their internal signal transduction pathways. TNF-R1 initiates the majority of TNF.s activities, which includes triggering apoptosis of certain tumor cells, mediating the inflammatory response and regulating immune function (Chen). Each pathway is characterized by TNF-induced formation of a multi-protein signaling complex at the cell membrane. TNF and TNF-R1 binding initiates a series of intracellular events that result in activation of the transcription factors NF kappa B and c-Jun. TNF and TNF-R1 binding triggers release of the 80 residue inhibitory protein silencer of death domains (SODD) from the C-terminal intracellular domain of TNF-R1. This domain interacts with TNF receptor-associated death domain (TRADD) which in turn recruits receptor-interacting protein (RIP) TNF-R-associated factor 2 (TRAF2) and Fas-associated death domain (FADD). These three proteins recruit enzymes responsible for initiating signaling events. For example, interaction of SODD with TRADD, and subsequent interactions with FADD initiates Caspase-8 mediated apoptosis. TRAF2 links TNF-R1 with stress activated protein kinase (SAPK) and p38 mitogen activated protein kinases via germinal center kinase (GCK) and receptor interacting protein (RIP). The cytoplasmic domain of TNF-R1 can directly interact with Jak kinases, thereby.

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