Types of Signaling Pathways

Cell Biology

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6gqxyinyqmcv3gcrk4bq 180409 s0 hashmi uzair types of signalling pathways intro
03:38
Types of Signaling Pathways
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09:33
TGF-ß/SMAD Pathway
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10:57
JAK-STAT Pathway
Ntxsl3i0qyavakwwh492 180409 s3 hashmi uzair rtk and ras map kinase pathway
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RTK and Ras/Map Kinase Pathway
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09:35
Ras/Map Kinase Pathway
Osbst5unrueemrz8adbc 180409 s5 hashmi uzair mechanisms of activation of remaining signalling pathways
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Mechanisms of Activation of Remaining Signalling Pathways

Lecture´s Description

TGF-ß/SMAD Pathway

The elucidation of Types of Signaling Pathways is delivered in this Sqadia video. Each TGFß isoform is synthesized as part of a larger precursor that contains a pro-domain. This domain is cleaved from but remains noncovalently associated with the mature domain after the protein is secreted. Most secreted TGFß is stored in the extracellular matrix as a latent, inactive complex containing the cleaved TGFß precursor and a covalently bound TGFß -binding protein called Latent TGFß Binding Protein, or LTBP. Binding of LTBP by the matrix protein thrombospondin or by certain cell-surface integrins triggers a conformational change in LTBP that causes release of the mature, active dimeric TGFß. Alternatively, digestion of the binding proteins by matrix metalloproteases can result in activation of TGF. The transcription factors downstream from TGFß receptors in Drosophila and the related vertebrate proteins are now called Smads. Three types of Smad proteins function in the TGFß signaling pathway: R-Smads, co-Smads, and I-Smads. In some cells, TGFß binds to the type III TGFß receptor (RIII), which presents it to the type II receptor (RII). In other cells, TGFß binds directly to RII, a constitutively phosphorylated and active kinase. There are two other SMADs which complete the SMAD family, the inhibitory SMADs (I-SMADS), SMAD6 and SMAD7 (SnoN and Ski). They play a key role in the regulation of TGF beta signaling and are involved in negative feedback. SMAD7 competes with other R-SMADs with RI and prevents their phosphorylation.

JAK-STAT Pathway

The cytosolic domain of RTKs contains a protein tyrosine kinase catalytic site, whereas the cytosolic domain of cytokine receptors associates with a separate JAK kinase. In both types of receptor, ligand binding causes a conformational change that promotes formation of a functional dimeric receptor, bringing together two intrinsic or associated kinases. The activated kinase then phosphorylates other tyrosine residues in the receptor’s cytosolic domain. Cytosolic proteins with SH2 or PTB domains can bind to specific phosphotyrosine residues in activated RTKs or cytokine receptors. Certain RTKs and cytokine receptors utilize multidocking proteins such as IRS-1. Phosphorylation of the IRS-1 by receptor kinase activity creates additional docking sites for SH2-containing signaling proteins. Four major pathways can transduce a signal from the activated, phosphorylated EpoR-JAK complex i.e  STAT5GRB2 or Shc, Phospholipase Cγ,  and PI-3 kinase.  JAK phosphorylates several tyrosine residues on the receptor’s cytosolic domain. After an inactive monomeric STAT transcription factor binds to a phosphotyrosine in the receptor, it is phosphorylated by active JAK. Phosphorylated STATs spontaneously dissociate from the receptor and spontaneously dimerize. There are Two mechanisms for terminating signal transduction from the erythropoietin receptor (EpoR), one is  JAK2 deactivation induced by SHP1 phosphatase, and the other is  Signal blocking and protein degradation induced by SOCS proteins.

RTK and Ras/Map Kinase Pathway

Receptor tyrosine kinases (RTKs), which bind to peptide and protein hormones, may exist as preformed dimers or dimerize during binding to ligands. Ligand binding leads to activation of the intrinsic protein tyrosine kinase activity of the receptor and phosphorylation of tyrosine residues in its cytosolic domain. The activated receptor also can phosphorylate other protein substrates. Ras is an intracellular GTPase switch protein that acts downstream from most RTKs. Like Gα, Ras cycles between an inactive GDP-bound form and an active GTP-bound form. Ras cycling requires the assistance of two proteins, a guanine nucleotide–exchange factor (GEF) and a GTPase-activating protein (GAP). RTKs are linked indirectly to Ras via two proteins: GRB2, an adapter protein, and Sos, which has GEF activity. The SH2 domain in GRB2 binds to a phosphotyrosine in activated RTKs, while its two SH3 domains bind Sos. Binding of Sos to inactive Ras causes a large conformational change that permits release of GDP and binding of GTP, forming active Ras. Mutant Ras proteins are associated with many types of human cancer. Mutant Ras can bind GTP but cannot hydrolyze it and are permanently in the ‘on’ state and contribute to oncogenic transformation.

Ras/Map Kinase Pathway

In unstimulated cells, most Ras is in the inactive form with bound GDP; binding of a ligand to its RTK or cytokine receptor leads to formation of the active RasGTP complex. Activated Ras triggers the downstream kinase cascade culminating in activation of MAP kinase (MAPK). In unstimulated cells, binding of the protein to Raf stabilizes it in an inactive conformation. Interaction of the Raf N-terminal regulatory domain with Ras-GTP relieves this inhibition, results in dephosphorylation of one of the serine and leads to activation of Raf kinase activity. In the cytosol, MAP kinase phosphorylates and activates the kinase p90RSK, which then moves into the nucleus and phosphorylates the SRF transcription factor. After translocating into the nucleus, MAP kinase directly phosphorylates the transcription factor TCF. The receptors for yeast a and α mating factors are coupled to the same trimeric G protein. Ligand binding leads to activation and dissociation of the G protein. In the yeast mating pathway, the dissociated GβƳ activates a protein kinase cascade analogous to the cascade downstream of Ras that leads to activation of MAP kinase.  In unstimulated cells, PKB is in the cytosol with its PH domain bound to the catalytic domain, inhibiting its activity. The 3-phosphate groups serve as docking sites on the plasma membrane for the PH domain of PKB and another kinase, PDK1.

Mechanisms of Activation of Remaining Signalling Pathways

The NF-kB transcription factor regulates many genes that permit cells to respond to infection and inflammation.  In unstimulated cells, NF-kB is localized to the cytosol, bound to an inhibitor protein, I-kB. In response to extracellular signals, phosphorylation-dependent ubiquitination and degradation of I-kB in proteasomes releases active NF-kB, which translocates to the nucleus. Upon binding to its ligand Delta on the surface of an adjacent cell, the Notch receptor protein undergoes two proteolytic cleavages. The released Notch cytosolic segment then translocates into the nucleus and modulates gene transcription. Presenilin 1, which catalyzes the regulated intramembrane cleavage of Notch, also participates in the cleavage of amyloid precursor protein (APP) into a peptide that forms plaques characteristic of Alzheimer’s disease. Wnt signaling begins when a Wnt protein binds to the N-terminal extra-cellular cysteine-rich domain of a Frizzled (Fz) family receptor. These receptors span the plasma membrane seven times and constitute a distinct family of G-protein coupled receptors (GPCRs). However, to facilitate Wnt signaling, co-receptors may be required alongside.

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