reseptor tirosin kinase.pptx
TRANSCRIPT
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RESEPTOR TIROSIN KINASE
Sarmoko
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Introduction
• Receptor tyrosine kinases (RTK)s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones.
• Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins.[1]
• Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer.[2] [1] Robinson DR, Wu YM, Lin SF. (2000)
[2] Zwick, E. Bange, J. Ullrich, A. (2001)
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I Transduksi Signal Langsung
• Stimulasi reseptor permukaan sel secara langsung mengaktivasi suatu protein yang mempengaruhi aktivitas transkripsi. Sistem transduksi langsung ini umum terjadi pada signaling oleh SITOKIN seperti interleukin dan interferon.
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Aktivasi
• Adanya ikatan antara sitokin dengan reseptornya akan memacu aktivitas aktivator transkripsi yang disebut STAT (signal transducer and activator of transcription).
• Lalu, aktivasinya melalui JAK (Janus kinase), melalui proses autofosforilasi hingga mengaktifkan STAT.
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Transduksi Signal Melalui Seri Kompleks Protein
• Pengertian: yaitu sistem transduksi signal yang melibatkan satu seri aktivasi protein-protein menuju aktivasi faktor transkripsi sehingga mempengaruhi ekspresi gen.
II
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Sistem Ras
• Protein yang termasuk dalam keluarga Ras berperan penting sebagai intermediet jalur transduksi signal yang terinisiasi oleh adanya aktivasi Reseptor Tirosin Kinase (RTK). Ligan untuk RTK:
• NGF (nerve growth factor)• PDGF (platelet-derived growth factor)• FGF (fibroblast growth factor)• EGF (epidermal growth factor)• Insulin
a
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• Ras merupakan protein GTP-binding switch yang merubah antara keadaan aktif (saat mengikat GTP, Guanosin Tripospat) dan keadaan inaktif (saat mengikat GDP, Guanosin Dipospat).
• Aktivasi Ras difasilitasi oleh Guanin Exchange Factor (GEF) yang membantu pelepasan GDP dari Ras.
• Sementara GAP (GTP-ase activating protein) terikat, terjadi hidrolisis GTP yang terikat Ras hingga menjadi Ras-GDP.
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Sistem MAPK
Sistem multifungsional mitogen-activated protein kinase (MAPK) signaling meliputi fungsi yang terpisah untuk megatur proses seluler yang berbeda seperti transkripsi gen, metabolisme, motilitas, proliferasi sel, apoptosis, plastisitas sinaptik dan long-term memory
b
*Mitogen, suatu polipeptida/protein yang dapat mempengaruhi ekspresi gen sehingga mengubah sifat fisiologi sel.
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Kelompok besar MAPK
Perbedaan downstream efektor diaktivasi oleh komponen MAPK akhir, yang digubungkan dengan 3 kelompok besar dalam MAP kinase signaling, yaitu:
• Kelompok extracelluler signal-regulated kinases (ERKs)
• Kelompok p38 MAK kinase• Kelompok c-Jun N-terminal kinase (JNKs).
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MAPK signalling toolkit
• MAP kinase (MAPK)
• MAP kinase kinase (MKK atau MEK)
• MAP kinase kinase kinase (MKKK atau MEKK)
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CROSSTALK
RAS RAF MAP KINASE
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The Ras-Raf-MAP kinase pathway
Tyr-P
Grb2
SH3 domains
Proline-rich regions (-PXXP-)
Sos Ras(inactive)
GDP GTP
PiRas(active)
Raf
MEK
MAP kinase
P
PP
DNA
Nucleus
MAP kinase
PPfos junPP
Increase gene expression
SH2 domain
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VERSI LAIN
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CROSSTALK
RAS RAF MAP KINASE
DAN
JAK/STAT
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Mekanisme Kerja Obat
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Mekanisme Rilis Insulin
• Glukosa yang masuk dimetabolisme (Glikolisis) ATP ↑• Kanal KATP menutup• Depolarisasi• Kanal Ca2+ terbuka• [Ca2+ intraseluler] ↑• Sekresi insulin
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Reseptor Insulin
• Aktivasi reseptor insulin menghasilkan efek:
• 1. translokasi GLUT-4 ke membran sel untuk mentransport glukosa masuk ke dalam sel
• 2. Sintesis lipid (anti lipolisis)• 3. Sintesis glikogen di hepar
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