* Signaling receptors, typically located on the cell surface, generally initiate signaling in the cytosol, followed by a nuclear phase.
* Many different types of signaling receptors contribute to innate and adaptive immunity, the most prominent category being immune receptors that belong to a receptor family in which non-receptor tyrosine kinases phosphorylate tyrosine-containing ITAM motifs on the cytoplasmic tails of proteins in the receptor complex.
* Some of the other types of receptors of interest in immunology include those of the receptor tyrosine kinase family, nuclear receptors, heterotrimeric G protein-coupled serpentine receptors, and receptors of the Notch family.
* Antigen receptors on T and B cells are members of the immune receptor family.
* Antigen receptors can produce widely varying outputs, depending on the affinity and valency of the antigen that can recruit different numbers of ITAMs.
* Antigen receptors use coreceptors to enhance signaling. Coreceptors bind to the same antigen complex that is being recognized by the antigen receptor.
* Signaling from antigen receptors can be attenuated by inhibitory receptors.
* The TCR complex is made up of the TCR a and p chains that contribute to antigen recognition and the ITAM-containing signaling chains CD3 y 8, and e as well as the Z homodimer. The CD3 chains each contain one ITAM, whereas each Z chain contains three ITAMs.
* TCR ligation results in tyrosine phosphorylation of CD3 and Z ITAMs by Src family kinases and the recruitment of ZAP-70 to the phospho-ITAMs, each SH2 domain of ZAP-70 binding to one phos-phorylated tyrosine of the ITAM.
* Activated ZAP-70 phosphorylates tyrosine residues on adaptors, and downstream enzymes are recruited to the signalosome.
* Enzymes that mediate the exchange of GTP for GDP on small G proteins such as Ras and Rac help initiate MAP kinase pathways. These pathways lead to the induction or activation of transcription factors such as Jun and Fos, components of the AP-1 transcription factor.
* Activation of PLCyl leads to the release of IP3 from PIP2, and IP3 induces release of calcium from intracellular stores. Depletion of calcium from intracellular stores facilitates the opening of CRAC, a store-operated channel on the cell surface that maintains the raised intracellular calcium levels. Calcium binds to calmodulin and activates downstream proteins including calcineurin, a phospha-tase that facilitates the entry of the NFAT transcription factor into the nucleus.
* Diacylglycerol is generated in the membrane when PLCyl releases IP3 from PIP2. DAG can activate PKC-0, which among other things can contribute to NF-kB activation .
* A lipid kinase called PI3-kinase converts PIP2 to PIP3. PIP3 can recruit and activate PH domain-containing proteins to the plasma membrane. PIP3 activates Itk in T cells and Btk in B cells. It activates PDK1, a kinase that can phosphorylate a downstream kinase called Akt that mediates cell survival.
* Costimulatory receptors initiate signaling separately from antigen receptors, but signaling outputs from antigen receptors and costimulatory receptors synergize in the nucleus. The major costimu-latory receptor in T cells is CD28.
* T cell signaling can be inhibited by phosphatases that may be recruited by inhibitory receptors such as CTLA-4 and PD-1.
* T cell signaling is also attenuated by ubiquitin E3 ligases that can contribute to the monoubiquitina-tion and lysosomal degradation of activated signaling proteins.
* The B cell receptor is made up of membrane-bound immunoglobulin and an associated disulfide-linked Iga and IgP heterodimer. Both Iga and IgP contain ITAM motifs in their cytoplasmic tails. Signaling pathways linked to the BCR are broadly similar to signaling pathways downstream of the TCR.
* The coreceptor for the BCR is CD21, also known as CR2 (complement receptor type 2).
* Attenuation of immune receptor signaling in B cells, T cells, and NK cells, among others, is mediated by inhibitory receptors that frequently contain inhibitory tyrosine-containing motifs or ITIMs in their cytoplasmic tails.
* Another important mechanism of signal attenuation involves the ubiquitination of signaling proteins by E3 ubiquitin ligases.
* Cytokine receptors can be divided into a few broad categories based on structural considerations and mechanisms of signaling.
* Many cytokine receptors use non-receptor tyrosine kinases called JAKs to phosphorylate transcription factors called STATs.
* Some cytokine receptors such as those of the TNF receptor family activate either canonical or non-canonical NF-kB signaling.
* Canonical NF-kB signaling is activated downstream of many receptors, including TNF receptor family cytokine receptors, TLRs and IL-1R family members, and antigen receptors. The pathway involves activation of IKKp in the IKK complex, phosphorylation of the IKBa inhibitor by activated IKKP, ubiquitination and proteasomal degradation of IKBa, and transport of NF-kB to the nucleus.
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