Section 1.3.pdf

Section 1 Hormones Receptors and Rhythms Part 3 1st step of phosphorylation kinase: phosphorylation on tyrosine Tyrosine Kinase Receptors (RTK) typically, function in dimeric fashion: receptors function in pairs, sometimes a signal comes in, binds to one receptor and brings the other receptor to do...

Section 1 Hormones Receptors and Rhythms Part 3 1st step of phosphorylation kinase: phosphorylation on tyrosine Tyrosine Kinase Receptors (RTK) typically, function in dimeric fashion: receptors function in pairs, sometimes a signal comes in, binds to one receptor and brings the other receptor to do the complex sometimes 2 receptors together signal initiation requires 2 receptors binding to the ligand Receptors with intrinsic kinase activity Receptors that recruit a kinase don’t have their own intrinsic kinase activity when bound to ligand, able to recruit a tyrosine kinase Receptors with intrinsic tyrosine kinase activity insulin receptor: most studied one Insulin Receptor – an RTK with intrinsic tyrosine kinase activity receptor processed so protein is cleaved and reversed and brought to functional status v Hetero-tetrameric structure (2 α and 2 β chains held together by S-S bonds) v MW 400 kDa v Each dimer is processed from a single precursor protein: Formation of disulfide bonds and proteolytic cleavage v β subunit about 618 a.a.: Ectodomain 193 a.a., transmembrane domain 23 a.a., chain mostly ectodomain cytoplasmic domain 402 a.a. alpha beta chain bigger than alpha v Between 100 and 200 000 receptors per cell (highest in adipocytes and hepatocytes) cells of adipose tissue and cells of liver v Homology with the IGF-I receptor insulin like growth factor Insulin Receptor – an RTK with intrinsic tyrosine kinase activity Autophosphorylation of intracellular domain of the receptor IRS participate in other RTK too, not only insulin Docking and phosphorylation of IRS-1 or IRS-2 (insulin receptor substrate) Activation of two major signal pathways (MAPK & PIP3) PIP3 NOT THE SAME THING AS IP3 RTK Signaling through MAPK pathway (also called ERK1/2 pathway) RAS - GTPase Ras: GTPase enzyme, active and immediately gets inactive (GTP —> GDP) after activating Ras MEK simultaneously activates ERK1 and 2 (similar in size and aa) —> do same type of signalling v ERK1/2 phosphorylating TFs (Elk, SRF, Ets, c-Fos) is well defined mechanism of regulation of gene expression can change other proteins function in cytoplasm and nucleus —> kinase v ERK2 can bind to DNA and inhibit other TFs from binding TF only in nucleus mitogen activated protein kinase MAPK pathway includes a large complex family of proteins MEK1/2: most studied one Need to know that MAPK are phosphorylated by MAPKK, etc. mitogenesis When we talk about insulin change and TG degradation into FA: enzymes responsible for lipid mobilization are activated by MAPK pathways mitogen stress stress RAF1/A/B MLK DKL MEK1/2 MKK4/7 MKK3/4/5 MAPKK kinase MAPKKK MAPK kinase MAPKK MAPK ERK1/2 JNK1/2/3 p38 (lower case) P38⍺/β/𝛾/𝞭 MAPK: main kinase that chance cellular response Proliferation/differentiation/apoptosis/ gene expression/cell motility/metabolism For now, focus on step 1 + that it activates PKB RTK Signaling through PIP3 PIP2: GPCR signaling regulation of glucose metabolism 80 RTK Signaling through PIP3 Here, no cleaving of PIP2 in DAG + IP2, here we gets PIP3 (kinase activity) Phosphatidylinositol (4,5)-bisphosphate Phosphatidylinositol (3,4,5)-trisphosphate 81 RTK Signaling through PIP3 82 Receptors with recruited tyrosine kinase activity vBest known in this class are the receptors for growth hormone (GH), prolactin (PRL), interferon and leptin vMany cytokine/haemopoietic receptors (over 20 members) Receptors with recruited tyrosine kinase activity v GH has two binding sites and binds sequentially to two receptor molecules v Dimerization of the cytoplasmic regions initiates signal transduction v First step is to recruit JAK-2 (JAK = Janus Kinase) don’t have their own enzyme activity, recruits their kinase JAK-STAT pathway JAK family: JAK1 JAK2 JAK3 TYK2 v Recruitment of JAK2: phosphorylates itself, the receptor and other proteins v Branch 1: Activation of the transcription regulatory proteins, STAT (4 isoforms) v Branch 2: Activation of the MAPK pathway (as in insulin signaling, but here JAK2 plays the role of IRS1) v Branch 3: Activation of PIP3 pathway JAK-STAT pathway STAT: signal transducer and activator of transcription need 2 types of STAT: 1 and 2 binds to upstream region (promoter region) promoting gene expression Serine-Threonine kinase receptor (RSTK) Serine and threonine phosphorylation cascade: phosphorylated together typically dimerization of 2 different R (TGF-BRI and II): initiation = heterodimers —> phosphorylation of cytoplasmic domain regulatory co partners inhibitory need it to enter the nucleus (not phosphorylated) v Best known in this class: TGF-β v Smad proteins are the mediators of TGF-β signaling v Smad proteins regulate gene expression Intracellular Receptors for Hormones v Steroid hormones and thyroid hormones bind to a family of intracellular receptors, which are structurally related v The intracellular receptors are located in the cytoplasm or the nucleus v The receptors function as transcription factors hormone regulated transcription factors v Response is slow since transcription and translation of can only function through regulating gene expression (complex, so proteins are necessary bcslower vs kinase regulate gene expression, but can change enzymatic expression in cytoplasm, so action is quicker) Classes of NR ligands need intracellular receptors called nuclear receptor Nuclear Receptor Domains 49 nuclear receptor (don’t need to know all of them) : typical structure Thyroid hormone 1st discovered and after estrogen : structural similarity small sequence of aa that can bind directly to a specific sequence on DNA typically function as dimers (reads 2 sequences), but can work as monomer (reads 1 sequence) need to enter the nucleus, most of them have this unique signal to go to the nucleus bc hormone dependant (hormone dependant) Nuclear Receptor Signaling Mechanism Hormone has to enter the cell As soon as it enters the cell, hormone go and bind to the nuclear receptor (TF = binds to specific sequence = elements) HRE=hormone response element Regulates transcription of a target gene 1st thing required for it to function Nuclear Receptor DNA binding Domain Typically function as homodimers or sometimes heterodimers same sequence different sequences are involved in formation/recruitment of pre-initiation complex (GTF = general transcription factors required for all gene expression —> required for pol II to move to and transcribe) regulators = transcription factors (in this case, the one binding to HRE) interacts with either co-activators and co-repressors: impact on gene expression (increase and decrease) Nuclear Receptor Regulation of Gene Expression Cells respond by integrating all the multiple signals Signal interaction Many signaling pathways overlap, resulting in a complex signaling network