Biologi Sel: Jalur Sinyal Utama
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Apa salah siji jalur sinyal utama sing kalebu ing konten?

  • Ras/Raf
  • AMPK
  • Wnt
  • JAK/STAT (correct)

    • Jalur sinyal Ras/MAPK iku salah siji jalur sinyal utama.

    True (A)

    Sebutno siji fungsi utama jalur PI3K/Akt!

    Regulasi pertumbuhan sel

    Jalur _____ digunakake kanggo ngatur translasi protein.

    <p>JAK/STAT</p> Signup and view all the answers

    Padukan jalur sinyal karo fungsi utama:

    <p>JAK/STAT = Ngatur proses imun Ras/MAPK = Ngatur pertumbuhan sel PI3K/Akt = Regulasi metabolisme Ras/ERK = Signal transduction</p> Signup and view all the answers

    Apa fungsi saka DLL4 ing sistem Notch?

    <p>Ngaktifake sinyal NF-κΒ kanggo ningkatake VEGF (D)</p> Signup and view all the answers

    S2 cleavage majeng nalika Delta ora mbantu Notch.

    <p>False (B)</p> Signup and view all the answers

    Sapa sing diarani NOTCH1, NOTCH2, NOTCH3, lan NOTCH4?

    <p>Gen-gen keluarga Notch</p> Signup and view all the answers

    DLL1 ngatur __________ lan komunikasi antar sel.

    <p>diferensiasi sel</p> Signup and view all the answers

    Pasang gen keluarga Delta karo fungsine:

    <p>DLL1 = Nandhesake diferensiasi sel DLL3 = Nyepetake pertumbuhan sel JAG1 = Ningkatake angiogenesis JAG2 = Nglakokake kelangsungan urip sel</p> Signup and view all the answers

    Apa peranan utama saka NOTCH intracellular domain (NICD)?

    <p>Translokasi menyang nukleus lan ngaktifake transkripsi gen (C)</p> Signup and view all the answers

    Alagille syndrome nyebabake perkembangan abnormal ing beragam organ.

    <p>True (A)</p> Signup and view all the answers

    S1 cleavage yaiku proses sing kedadeyan mung sawise translasi __________.

    <p>Notch</p> Signup and view all the answers

    Apa fungsi sitokin?

    <p>Ngomunikasi antar sel (B)</p> Signup and view all the answers

    Sitokin bisa nyebrang membran sel kanggo ngirim sinyal.

    <p>False (B)</p> Signup and view all the answers

    Sebutake 4 anggota JAK sing kasedhiya.

    <p>JAK1, JAK2, JAK3, TYK2</p> Signup and view all the answers

    JH2 yaiku domain _________ ing JAK.

    <p>autoinhibitory</p> Signup and view all the answers

    Cocokna jinis sitokin lan tipe sinyal JAK/STAT:

    <p>Interleukins (IL) = JAK/STAT Interferons (IFN) = JAK/STAT Tumor Necrosis Family (TNF) = JAK/STAT Transforming growth factor (TGF) = Non-JAK/STAT</p> Signup and view all the answers

    Apa akibat mutasi V617F ing JAK2?

    <p>Nambah produksi sel progenitor myeloid (B)</p> Signup and view all the answers

    Ruxolitinib iku inhibitor sing ngganggu situs ikatan ATP ing JAK1 lan JAK2.

    <p>True (A)</p> Signup and view all the answers

    Apa sing dianggep minangka sinyal lokasi nuklir ing STAT?

    <p>Nuclear localization signal (NLS)</p> Signup and view all the answers

    Sitokin sensitif _______ lan _______ ngandhut elemen respons khusus.

    <p>interferon, gamma</p> Signup and view all the answers

    Apa jinis kinases ing JAK?

    <p>Tyrosine kinases (C)</p> Signup and view all the answers

    Apa fungsi utamane PIAS ing jalur sinyal?

    <p>Nglawan ikatan DNA (C)</p> Signup and view all the answers

    Ras yaiku protein G cilik sing ora perlu modifikasi lipid kanggo aktif.

    <p>False (B)</p> Signup and view all the answers

    Sebutna telu jinis receptor tyrosine kinase!

    <p>Insulin receptor, epidermal growth factor receptor, platelet-derived growth factor receptor</p> Signup and view all the answers

    Sos minangka Ras _____ yang paling utama.

    <p>GEF</p> Signup and view all the answers

    Pasangake hormon utawa unsur karo efek utawa karakteristik sing bener:

    <p>Grb2 = Nggandheng IRS1 lan Sos KSR = Supressor kinase Ras ERK = Ngaktifake faktor transkripsi JNK = Diaktifake dening stres</p> Signup and view all the answers

    Yen Ras onkogenik, apa sing kedadeyan ing aktivitas GTPase?

    <p>GTPase ora bisa aktif (B)</p> Signup and view all the answers

    Gen c-Jun lan c-Fos yaiku gen respon awal sing onkogenik.

    <p>True (A)</p> Signup and view all the answers

    Apa sing dadi peran ERK ing jalur MAPK?

    <p>ERK ngaktifake faktor transkripsi.</p> Signup and view all the answers

    Jalur _____ iki diaktifake dening faktor mitogen kaya Ras.

    <p>MAPK</p> Signup and view all the answers

    Pasangake mutasi onkogenik karo jinis kanker:

    <p>V600E = Melanoma H-Ras = Kanker tiroid K-Ras = Kanker pankreas N-Ras = Kanker hematologis</p> Signup and view all the answers

    Apa jenis protein sing diaktifake dening Ras sawise GTP nyambung?

    <p>Raf-1 (A)</p> Signup and view all the answers

    MAPK bisa dipengaruhi dening kombinasi sinyal sing dikirim dening receptor.

    <p>True (A)</p> Signup and view all the answers

    Apa sing ditindakake scaffold proteins marang jalur MAPK?

    <p>Ngatur keefektifan sinyal.</p> Signup and view all the answers

    Proteins sing ngatur jalur degradasi Ubiquitin yaiku _____ dan PTP.

    <p>SOCS</p> Signup and view all the answers

    Sapa subunit katalitik saka Class I PI3K?

    <p>p110 (A)</p> Signup and view all the answers

    Aktivasi Akt/PKB mbutuhake fosforilasi ing Thr308 lan Ser473.

    <p>True (A)</p> Signup and view all the answers

    Apa peran utama mTORC1 nalika ditemokake ing sel?

    <p>Promosi proliferasi</p> Signup and view all the answers

    PTEN, sing minangka _____, ngilangi fosfat saka PIP3.

    <p>suppressor tumor</p> Signup and view all the answers

    Pasang protein karo peranane:

    <p>PI3K = Fosforilasi PIP2 Akt = Mediator hulu PI3K mTORC1 = Aktivasi proliferasi PTEN = Inhibisi sinyal PIP3</p> Signup and view all the answers

    Sapa sing ngatur siklus sel lan pertumbuhan liwat sinyal montor?

    <p>mTORC1 (A)</p> Signup and view all the answers

    Rheb-GTP iku aktif lan bisa nyebabake aktivasi mTORC1.

    <p>True (A)</p> Signup and view all the answers

    Apa sing kedadeyan nalika AMPK aktif?

    <p>Inhibisi pertumbuhan</p> Signup and view all the answers

    Wnt minangka protein sing dirilis saka gen _____.

    <p>Drosophila Wingless (Wg)</p> Signup and view all the answers

    Apa peran utama GSK-3β ing jalur Wnt?

    <p>Fosforilasi β-catenin (A)</p> Signup and view all the answers

    Ras ora bisa aktifake PI3K.

    <p>False (B)</p> Signup and view all the answers

    Apa sing kedadeyan nalika β-catenin akumulasi ing inti sel?

    <p>Promosi transkripsi gen</p> Signup and view all the answers

    MTOR yaiku _____ target saka Rapamycin.

    <p>mammal</p> Signup and view all the answers

    Protein APC (Adenomatous Polyposis Coli) iku aji tumrap apa?

    <p>Penekan tumor (A)</p> Signup and view all the answers

    Mutasi ing β-catenin bisa nggawe luwih gampang terdegradasi.

    <p>False (B)</p> Signup and view all the answers

    Ing jalur sinyal Wnt, apa sing kedaden nalika β-catenin akumulasi ing inti sel?

    <p>Nglanjutake perkembangan kanker</p> Signup and view all the answers

    Interaksi β-catenin karo ____ penting kanggo adhesi sel-sel.

    <p>E-cadherin</p> Signup and view all the answers

    Pasangake konsep karo deksripsi sing bener:

    <p>Notch = Sinyal juxtacrine Delta = Ligand kanggo Notch GSK-3β = Regulator kunci ing jalur Wnt p53 = Penekan tumor</p> Signup and view all the answers

    Apa sing ndadekake mutasi β-catenin resisten kanggo degradasi?

    <p>Disruptsi fosforilasi (A)</p> Signup and view all the answers

    Sinyal Notch njaga supaya sel-sel ora beda dadi sel saraf ing mamalia.

    <p>True (A)</p> Signup and view all the answers

    Ing konteks sinyal Notch, apa sing ditemtokake nalika salah sawijining sel "menang"?

    <p>Ekspresi Delta luwih akeh</p> Signup and view all the answers

    Study Notes

    Major Signaling Pathways

    • JAK/STAT pathway
    • Ras/MAPK pathway
    • PI3K/Akt pathway

    Cytokine Signaling through the JAK/STAT Pathway

    • Cytokines are small proteins (5-25 kDa)
    • Released by cells to enable cell-cell communication
    • Do not cross cell membranes
    • Signal through binding to specific receptors on the cell surface
    • Cytokine families include: Interleukins (IL), Interferons (IFN), and Tumor Necrosis Factor (TNF) family, Transforming growth factor (TGF)

    Cytokine Receptors

    • Hetero-dimers or trimers
    • Crucial for immune regulation
    • Different cytokines are produced by different cell types (e.g., IL-2 by T cells and DCs)
    • Different receptors bind different cytokines and activate different JAKs and STATs

    JAK/STAT Signaling

    • JAKs (Janus kinases) are kinases
    • Four members: JAK1, JAK2, JAK3, and TYK2
    • Two kinase domains (JH1/JH2)
    • JH2 is the autoinhibitory domain
    • SH2 domain allows interaction with cytokine receptors
    • FERM domain
    • Receptors are not stable at the membrane without JAKs

    Cytokine Signaling through the JAK-STAT Pathway (Mechanism)

    • Cytokine-mediated receptor dimerization
    • JAK tyrosine residues are phosphorylated
    • STATS recruitment and JAK-mediated phosphorylation
    • STATS dimerization
    • Transcription/mRNA translation
    • Transcription/ translation in cytokine-responsive gene

    Signal Transducer and Activator of Transcription (STAT)

    • Nuclear localization signal (NLS)
    • Tyrosine (Y) and serine (S) residues are phosphorylated in response to extracellular stimuli
    • Interaction sites for various transcriptional co-activators (green) and co-repressors (red)

    STATs bind to DNA to promote gene transcription

    • DNA sequences (e.g., CRE, ISRE, GASs) are found in the promoters of regulated genes and are involved in cytokine response and interferon (Type I, II, and III)
    • Specific sequences are associated with particular type of interferons

    IFNs activate unique gene transcription

    • Different types of interferons utilize different JAK/STAT combinations to activate unique gene transcription and promote immune functions
    • Type I IFNs use IFNAR1 and IFNAR2 receptors with specific JAK and STAT combinations
    • Type II IFNs use IFNGR2 receptor with specific JAK and STAT combinations
    • Type III IFNs use IFNLR1 and IL-10RB receptor with specific JAK and STAT combinations

    Different cytokine receptors can activate different JAKs and STATS

    • Different cytokine receptors activate specific combinations of JAKs and STATs, leading to diverse downstream signaling pathways.

    Mutations in JAK2

    • JAK2 mutations (e.g., V617F) are associated with myeloproliferative neoplasms
    • Destabilizes the interaction between JH2 and JH1 domains
    • Results in overproduction of myeloid progenitor cells
    • Ruxolitinib (Jakafi) is a potent inhibitor

    Structure and activation of JAK2

    • Mutation allows for partial activation
    • Cytokines activation result full activation of the kinase (e.g., erythropoietin, thrombopoietin)
    • These cytokines promote blood development

    Turning JAK/STAT Signaling Off

    • PIAS (protein inhibitor of activated STAT) inhibits DNA binding
    • SOCS (suppressor of cytokine signaling) blocks STAT recruitment and inhibits JAK
    • Protein tyrosine phosphatases (PTPs) dephosphorylate JAK or STAT receptors

    Ubiquitin degradation pathway

    • Ubiquitin marks proteins for degradation in the proteasome
    • A multi-step pathway involving E1, E2, and E3 ubiquitin ligases

    Ras/MAPK Pathway

    • Ras is a small GTPase involved in cellular signaling
    • Molecular switch similar to Ga subunit in heterotrimeric G-protein
    • Most common oncogene
    • Three common types of Ras: HRas, KRas, and NRAS
    • Lipid modification critical for activity
    • MAPK is mitogen-activated protein kinases
    • Mitogen is a factor that stimulates cell growth

    Activation of Ras by Growth Factor Receptors

    • Tyrosine Kinase Receptors act as dimers to trigger trans-phosphorylation
    • Upon activation, a conformational change occurs
    • Examples include: Insulin receptor, epidermal growth factor, and platelet-derived growth factors

    Insulin Receptor Signaling Overview

    • Insulin binds to the insulin receptor, causing autophosphorylation
    • Receptor then phosphorylates IRS1
    • IRS1 activates Grb2, which activates Sos
    • Sos activates Ras, which activates Raf-1, causing a cascade
    • The activation of ERK occurs leading to the transcription of genes for cell division

    Adapter proteins

    • IRS1: insulin receptor substrate 1, recruits Grb1 when phosphorylated
    • Grb2: growth factor receptor bound 2, links IRS1 with Ras GEF Sos, binds Sos through SH3 domain

    Sos

    • Major Ras GEF
    • Drosophila orthologue of "son-of-sevenless"
    • Regulates development of 7th central photoreceptor in Drosophila (detects UV light)
    • Receptor tyrosine kinase

    Activation of Ras

    • Sos causes GTP release from Ras, activating Ras
    • Ras activates Raf-1, a serine/threonine kinase
    • Raf-1 activates MEK
    • MEK activates ERK

    Activation of the MAPK cascade

    • Raf activates MEK
    • MEK activates ERK, with each step involve a phosphorylation
    • ERK moves to the nucleus
    • Phosphorylates key transcription factors

    Scaffold proteins keep MAPK modules together

    • Some proteins cluster some MAPK modules together for efficiency
    • Too many or few scaffold proteins can lead to decreased signal efficiency

    ERK activates transcription factors

    • ERK moves to the nucleus and phosphorylates key transcription factors
    • Transcription factors promote transcription of genes required for cell growth
    • Examples of Transcription factors: c-Fos, and c-Jun

    Other MAPK pathways

    • JNK (Stress-activated c-Jun N-terminal kinase) : Stress activated
    • p38: Stress activated and tends to promote apoptosis

    Generation of the AP-1 transcription factor

    • ERK and JNK phosphorylate c-Jun and c-Fos.
    • c-Fos and c-Jun dimerize to form AP-1
    • AP-1 is a transcription factor

    The same receptor can activate all or some of the MAPK pathways

    • The balance of signals dictates the fate of the cell (e.g., proliferation or apoptosis)

    Oncogenic Ras

    • Ras mutations occur in ~30% of human cancers
    • Single-base pair mutations generate amino acid changes
    • Blocks GTPase activity (resulting in constitutively activated Ras)
    • Untargetable

    Example Ras mutations

    • Specific mutations in different codons (12,13,61) for each HRAS, KRAS, NRAS.
    • Specific counts of these mutation for each cancer that related to.

    Oncogenic B-Raf mutations

    • V600E (class I) is the most common mutation in oncogenic B-Raf mutations
    • Causes kinase to be constitutively active
    • Particular common in melanoma and lung
    • Targetable with small molecules (e.g.,Vemurafenib, Dabrafenib)

    Phosphatidylinositol-3-kinase (PI3K) signaling overview

    • PI3K phosphorylates PIP2 to PIP3
    • PI3K pathway is activated by growth factors.
    • PI3k pathway affects mRNA translation, lipid synthesis, Nucleotide synthesis, and Autophagy

    PI3K: a family of proteins

    • Phosphorylates the 3’ position of phosphatidylinositols
    • Creates different phosphorylated products: (PtdIns4P, PtdIns(3,4)P2, PtdIns(4,5)P2, and PtdIns (3,4,5)P3).

    Class I PI3K have two subunits

    • p110 (catalytic subunit)
    • p85 (regulatory subunit)
    • p85 binds to Gβγ or phosphorylated receptors
    • Recruits p110 to the membrane
    • Phosphorylates PI(4,5)P2

    It's the PIP3 that is key for the next steps

    • PIP3 can bind to proteins with PH domains to recruit them to the plasma membrane, enabling activation
    • Akt/Protein Kinase B is a major downstream mediator of PI3K
    • Akt is recruited to the plasma membrane via its PH domain
    • Akt is phosphorylated by PDK1 and mTORC2
    • This double phosphorylation activates Akt

    Akt/PKB activation

    • Akt activation requires phosphorylation on Thr308 (by PDK1) and Ser473 (by mTORC2).
    • PDK1 and mTORC2 both have PH domains

    mTORC

    • TOR: Target of Rapamycin
    • mTOR: mammalian target of Rapamycin
    • mTORC: mammalian target of Rapamycin complex
    • Rapamycin: antifungal metabolite from Streptomyces hygroscopicus, potent immunosuppressant and anti-proliferative, specifically targets mTORC1.

    mTORC1(Raptor) and mTORC2 (Rictor)

    • Different mTORC1 and mTORC2 involve in protein synthesis, nucleotide synthesis, lipid synthesis, autophagy, glycolysis, actin/cytoskeleton organization pathways

    mTORC1 activation

    • Growth factors activate mTORC1 to promote proliferation
    • mTORC1 is associated with insulin, glucose, and amino acids

    AMPK (AMP Kinase) inhibits growth

    • AMPK inhibits growth when AMP levels are high, affecting glucose, amino acids, and growth factors signaling
    • AMP increased when cells do not have enough energy
    • Regulates cell cycle, survival, and processes

    Wnt signaling

    • WNT is a secreted protein from Drosophila's Wingless (Wg) gene
    • Directs the fate of cells
    • Directs patterning in central nervous system, respiratory and circulatory systems, and more epidermal structures

    Secreted protein (Wnt)

    • Wg does not act in a cell autonomously
    • In heterozygous flies, some rescues occur, due to the presence of normal protein rescuing neighboring cells

    Discovery of the int-1 oncogene

    • MMTV insertion mutation to identify oncogenes
    • MMTV promoter drives high expression of adjacent host genes
    • Int-1, a gene associated with the formation of mammary tumor
    • Int-1 has 54% similarity with Wg (Wingless)
    • Renamed Wnt

    Normal Wnt function

    • Found in the nervous system of embryos
    • KO mutations in mice eliminate brain patterning
    • Overexpression in Xenopus causes duplication of the frog embryo's axis
    • Wnt acts as an indicator to regulate brain patterning

    Gradient of Wnt allows anterior/posterior development

    • Wnt gradient affects development of anterior and posterior structures
    • Wnt/b-catenin signaling and retinoic acid level gradient affect cell type (anterior and posterior)
    • Wnt/b-catenin high/retinoic acid low to Wnt/b-catenin low/retinoic acid high

    Overview of Wnt signaling

    • Axin, APC, CK1α, GSK-3β form a destruction complex, important for the regulation of Wnt signaling
    • GSK-3β phosphorylates Ser33, Ser37, and Thr41 of β-catenin
    • Frizzled: receptor for Wnt
    • LRP: Low-density lipoprotein receptor-related protein
    • GSK-3β: glucogen synthase kinase-β
    • CK1α: Casein Kinase a
    • APC: Adenomatous Polyposis Coli

    Overview of Wnt signaling

    • Wnt binds LRP and Frizzled.
    • Dishevelled recruits the destruction complex to LRP to prevent degradation of β-catenin
    • Free β-catenin translocates to the nucleus to activate transcription factors (e.g., TCF/LEF) for gene expression

    GSK-3β

    • Phosphorylation inhibits GSK-3β activity
    • Serine/threonine kinase
    • Involved in inactivating glycogen synthase in insulin signaling
    • Involved in other signaling pathways like NF-kB, Hedgehog, and Notch

    Mutations in Wnt signaling

    • APC (Adenomatous Polyposis Coli) protein loss-of-function mutations are commonly associated with starting events of sporadic colorectal cancer
    • Familial adenomatous polyposis coli (FAP): inherited predisposition for cancer

    β-catenin

    • Two pools of β-catenin (cytoplasmic & membrane bound)
    • Cytoplasmic β-catenin is associated with GSK-3β, APC, and Axin complex
    • Membrane-bound β-catenin is associated with E-cadherin
    • Important for cell-cell adhesion
    • Phosphorylation from RTK can lead to activation

    β-catenin in cancer

    • Mutations in β-catenin can resist to degradation
    • Disrupt phosphorylation that induces degradation (e.g., Ser33, Ser37, and Thr41
    • Nuclear β-catenin accumulation correlate with colorectal cancer development
    • Cooperates with loss of p53 to promote carcinogenesis

    Notch signaling

    • Notch is a juxtacrine signaling pathway
    • Discovered in Drosophila in the 1910s
    • In mammals, Notch prevents differentiation of cells into neurons

    Multiple Notch and Delta family genes

    • Notch family genes (NOTCH1, NOTCH2, NOTCH3, NOTCH4)
    • Delta family genes (e.g., DLL1, DLL3, DLL4, JAG1, JAG2)

    Notch signaling overview

    • Activated Notch is cleaved into different pieces that associate at the membrane, releasing the cytoplasmic domain which translocates to the nucleus and activates gene transcription

    Regulation of S2 cleavage

    • The S2 cleavage site is normally hidden.
    • Upon binding to a ligand, a conformational change occurs, exposing the cleavage site.
    • Cleavage of the protein is performed by ADAMs enzymes (ADAM 10, ADAM 17, and ADAMTS1), which forms the NOTCH extracellular truncation (NEXT)

    The S3 cleavage

    • y-secretase cleaves Notch
    • The substrates are NOTCH receptors and amyloid precursor protein
    • The mechanism of y-secretase cleavage is not clearly understood.

    Other functions of Notch signaling

    • Notch signaling promotes organ production and damage repair
    • Affects cells differentiation
    • Stimulated in response to injuries

    Disease associated with Notch

    • Alagille syndrome: abnormal development of liver, heart, vasculature, bones, eyes, and maxillofacial dysplasia; chronic cholestasis in children; severe liver damage
    • Notch signaling is required for regeneration of liver cells

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    Description

    Pinter-pinter sira njawab pitakonan babagan jalur sinyal utama ing biologi sel. Sampeyan bakal nguji kawruh babagan jalur Ras/MAPK lan PI3K/Akt. Gabungake pengetahuanmu babagan fungsi utama jalur sinyal lan translasi protein.

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