Komunikasi Sel

Ikhtisar : Penyampaian Seluler Komunikasi sel ke sel penting untuk organisme multiseluler dan uniseluler Para ahli biologi menemukan beberapa mekanisme universal pengaturan seluler Kebanyakan sel seringkali berkomunikasi satu sama lain via sinyal kimiawi Misal, respon fight-or-flight dipicu molekul yang memberi sinyal epinefrin © 2011 Pearson Education, Inc.

Sinyaling Lokal dan Jarak jauh Sel pada organisme multiseluler berkomunikasi melalui pembawa pesan kimiawi Binatang dan tumbuhan mempunyai sel junctions langsung berkoneksi dengan sitoplasma sel didekatnya Pada pmberian sinyal lokal , sel binatang dapat berkomunikasi melalui kontak langsung, atau rekognisi sel-sel © 2011 Pearson Education, Inc.

Gap junctions antar sel binatang Plasmodesmata antar sel tumbuhan Figure 11.4 Membran Plasma Gap junctions antar sel binatang Plasmodesmata antar sel tumbuhan (a) Hubungan sel Figure 11.4 Communication by direct contact between cells. (b) Rekognisi sel-sel 4

Pada banyak kasus lainnya , komunikasi sel –sel menggunakan local regulators, molekul pembawa pesan berjalan pada jarak cukup dekat Pada pemberian sinyal jarak jauh, tumbuhan dan binatang menggunakan cairan kimiawi yang disebut hormon Kemampuan sel merespon sebuah sinyal tergantung ada atau tidaknya reseptor spesifik atas signal itu © 2011 Pearson Education, Inc.

Figure 11.5 Local signaling Long-distance signaling Target cell Electrical signal along nerve cell triggers release of neurotransmitter. Endocrine cell Blood vessel Neurotransmitter diffuses across synapse. Secreting cell Secretory vesicle Hormone travels in bloodstream. Target cell specifically binds hormone. Local regulator diffuses through extracellular fluid. Target cell is stimulated. Figure 11.5 Local and long-distance cell signaling by secreted molecules in animals. (a) Paracrine signaling (b) Synaptic signaling (c) Endocrine (hormonal) signaling 6

Neurotransmitter diffuses across synapse. Secreting cell Figure 11.5a Local signaling Target cell Electrical signal along nerve cell triggers release of neurotransmitter. Neurotransmitter diffuses across synapse. Secreting cell Secretory vesicle Figure 11.5 Local and long-distance cell signaling by secreted molecules in animals. Local regulator diffuses through extracellular fluid. Target cell is stimulated. (a) Paracrine signaling (b) Synaptic signaling 7

Long-distance signaling Figure 11.5b Long-distance signaling Endocrine cell Blood vessel Hormone travels in bloodstream. Target cell specifically binds hormone. Figure 11.5 Local and long-distance cell signaling by secreted molecules in animals. (c) Endocrine (hormonal) signaling 8

Tiga tahapan Pemberian Sinyal Sel : Pendahuluan Earl W. Sutherland menemukan bagaimana hormon epinefrin beraksi pada sel Sutherland mengatakan bahwa sel penerima sinyal berjalan melalui tiga proses Penerimaan Transduksi Respon © 2011 Pearson Education, Inc.

EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 Reception Receptor Figure 11.6-1 EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 Reception Receptor Figure 11.6 Overview of cell signaling. Signaling molecule 10

Relay molecules in a signal transduction pathway Figure 11.6-2 EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 Reception 2 Transduction Receptor Relay molecules in a signal transduction pathway Figure 11.6 Overview of cell signaling. Signaling molecule 11

Relay molecules in a signal transduction pathway Figure 11.6-3 EXTRACELLULAR FLUID CYTOPLASM Plasma membrane 1 Reception 2 Transduction 3 Response Receptor Activation of cellular response Relay molecules in a signal transduction pathway Figure 11.6 Overview of cell signaling. Signaling molecule 12

Penerimaan : sebuah molekul sinyal mengikat reseptor protein, menyebabkan perubahan bentuk Ikatan antara molekul sinyal (ligand) dan reseptor sangat bersifat spesifik Perubahan bentuk dalam reseptor seringkali merupakan inisial transduksi sinyal Kebanyakan reseptor sinyal merupakan membran plasma protein © 2011 Pearson Education, Inc.

Reseptor dalam Membran Plasma Kebanyakan sinyal molekul yang mudah larut dalam air mengikat tempat spesifik pada reseptor protein yang berjarak membran plasma Ada tiga tipe utama reseptor membran Reseptor G protein-berpasangan Reseptor tyrosine kinase Reseptor kanal ion © 2011 Pearson Education, Inc.

G-protein-coupled receptor (GPCRs) merupakan keluarga terbesar reseptor sel permukaan Sebuah GPCR merupakan reseptor membran plasma yang bekerja membantu G protein Protein G beraksi sebagai on/off switch: Jika GDP diikat protein G, maka protein G inaktif © 2011 Pearson Education, Inc.

Signaling molecule binding site Figure 11.7a Signaling molecule binding site Segment that interacts with G proteins Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors G protein-coupled receptor 16

G protein-coupled receptor Plasma membrane Activated receptor Figure 11.7b G protein-coupled receptor Plasma membrane Activated receptor Signaling molecule Inactive enzyme GTP GDP GDP CYTOPLASM G protein (inactive) Enzyme GTP 1 2 GDP Activated enzyme Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors GTP GDP P i 3 Cellular response 4 17

2-adrenergic receptors Molecule resembling ligand Figure 11.8 2-adrenergic receptors Molecule resembling ligand Plasma membrane Figure 11.8 Impact: Determining the Structure of a G Protein-Coupled Receptor (GPCR) Cholesterol 18

Fungsi abnormal RTK terkait dengan banyak jenis kanker Receptor tyrosine kinases (RTKs) merupakan reseptor membran yang melekatkan fosfat pada tyrosin Sebuah reseptor tyrosin kinase dapat memicu sinyal jaras multipel transduksi seketika Fungsi abnormal RTK terkait dengan banyak jenis kanker © 2011 Pearson Education, Inc.

Signaling molecule (ligand) Ligand-binding site Figure 11.7c Signaling molecule (ligand) Ligand-binding site  helix in the membrane Signaling molecule Tyrosines Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr Tyr CYTOPLASM Receptor tyrosine kinase proteins (inactive monomers) Dimer 1 2 Activated relay proteins Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors Cellular response 1 Tyr Tyr P Tyr Tyr P Tyr Tyr P P Tyr Tyr P Tyr Tyr Tyr Tyr P P P Cellular response 2 Tyr Tyr P Tyr Tyr P P Tyr Tyr P 6 ATP 6 ADP Activated tyrosine kinase regions (unphosphorylated dimer) Fully activated receptor tyrosine kinase (phosphorylated dimer) Inactive relay proteins 3 4 20

Suatu reseptor ligand-gated ion channel bertindak sebagai gerbang ketika reseptor berubah bentuk Ketika sebuah molekul sinyal sebagai ligand pada reseptor, gerbang memungkinkan ion spesifik seperti Na+ atau Ca2+, melewati kanal dalam reseptor © 2011 Pearson Education, Inc.

Signaling molecule (ligand) Figure 11.7d 1 2 3 Gate closed Ions Gate open Gate closed Signaling molecule (ligand) Plasma membrane Ligand-gated ion channel receptor Cellular response Figure 11.7 Exploring: Cell-Surface Transmembrane Receptors 22

Reseptor Intraseluler Reseptor protein intraseluler ditemukan dalam cytosol atau nukleus dari sel target Pembawa pesan kimiawi kecil atau hidofobik dapat langsung melintasi membran dan mengaktifkan reseptor Misal pembawa pesan hidrofobik hormon steroid dan thyroid pada binatang Sebuah reseptorr hormon kompleks yang diaktifkan dapat bertindak sebagai faktor teranskripsi, membalik pada gen spesifik © 2011 Pearson Education, Inc.

Hormone (testosterone) EXTRACELLULAR FLUID Figure 11.9-1 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein DNA Figure 11.9 Steroid hormone interacting with an intracellular receptor. NUCLEUS CYTOPLASM 24

Hormone (testosterone) EXTRACELLULAR FLUID Figure 11.9-3 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.9 Steroid hormone interacting with an intracellular receptor. NUCLEUS CYTOPLASM 25

Hormone (testosterone) EXTRACELLULAR FLUID Figure 11.9-4 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.9 Steroid hormone interacting with an intracellular receptor. mRNA NUCLEUS CYTOPLASM 26

Hormone (testosterone) EXTRACELLULAR FLUID Figure 11.9-2 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.9 Steroid hormone interacting with an intracellular receptor. NUCLEUS CYTOPLASM 27

Hormone (testosterone) EXTRACELLULAR FLUID Figure 11.9-5 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.9 Steroid hormone interacting with an intracellular receptor. mRNA NUCLEUS New protein CYTOPLASM 28

Transduksi: Cascades interaksi molekuler sinyal relay dari reseptor ke molekul target dalam sel Signal transduksi viasanya menyertai langkah bertahap Langkah bertahap akan meningkatkan sinyal: beberapa molekuldapat menghasilkan respon seluler besar Langkah bertahap menyediakan lebih banyak kesempatan untuk koordinasi dan regulasi seluler © 2011 Pearson Education, Inc.

Signal Transduction Pathways Molekul yang me relay sebuah sinyal dari reseptor untuk berespon merupakan molekul protein Seperti domino, satu molekul diaktivasi , akan menjalarkan pada protein lainnya Pada setiap langkah , sinyal ditransduksi ke dalam bentuk yang berbeda, biasanya pengubahan bentuk protein © 2011 Pearson Education, Inc.

Protein Fosforilasi dan defosforilasi Dalam banyak jaras , sinyal di transmisi oleh protein fosforilasi cascade Protein kinases transfer fosfat dari protein ATP, suatu proses yang disebut fosforilasi © 2011 Pearson Education, Inc.

Protein fosfatase rmenghilangkan fosfat dari protein, sebuah proses yang disebut defosforilasi Fosforilasi ini dan sistem defosforilasi beraksi sebagai molecular switch, memadamkan dan menghidupkan aktivitas sesuai kebutuhan © 2011 Pearson Education, Inc.

Activated relay molecule Figure 11.10 Signaling molecule Receptor Activated relay molecule Inactive protein kinase 1 Active protein kinase 1 Inactive protein kinase 2 ATP Phosphorylation cascade ADP Active protein kinase 2 P PP P i Figure 11.10 A phosphorylation cascade. Inactive protein kinase 3 ATP ADP P Active protein kinase 3 PP P i Inactive protein ATP ADP P Active protein Cellular response PP P i 33

Activated relay molecule Figure 11.10a Activated relay molecule Inactive protein kinase 1 Active protein kinase 1 Inactive protein kinase 2 ATP Phosphorylation cascade ADP Active protein kinase 2 P PP P i Inactive protein kinase 3 ATP Figure 11.10 A phosphorylation cascade. ADP Active protein kinase 3 P PP P i Inactive protein ATP ADP P Active protein PP P i 34

Molekul kecil dan Ion sebagai pembawa pesan Kedua Molekul sinyal ekstraseluler (ligand) mengikat reseptor merupakan pathway’s “first messenger” Second messengers molekul kecil, larut dalam air, nonprotein, atau ion yang disebar melalui sel dengan cara difusi Second messengers berpartisipasi dalam pathways diinisiasi oleh GPCRs dan RTKs Siklus AMP dan ion calcium merupakan second messengers yang umum © 2011 Pearson Education, Inc.

Siklus AMP Siklus AMP (cAMP) merupakan satu dari sekian banyak penggunaan second messengers Adenylyl cyclase, sebuah ensim dalam membran plasma , dikonversi ATP menjadi cAMP dalam merespon sinyal ekstraseluler © 2011 Pearson Education, Inc.

Figure 11.11 Adenylyl cyclase Phosphodiesterase Pyrophosphate AMP P i ATP cAMP AMP Figure 11.11 Cyclic AMP. 37

Adenylyl cyclase Pyrophosphate P P i ATP cAMP Figure 11.11a Figure 11.11 Cyclic AMP. ATP cAMP 38

Phosphodiesterase AMP cAMP H2O H2O Figure 11.11b Figure 11.11 Cyclic AMP. cAMP AMP 39

Banyak sinyal molekul memicu pembentukan cAMP Komponen lainnya dari jaras cAMP merupakan G protein, G protein-coupled receptors, dan protein kinases cAMP biasanya mengaktifkan protein kinase A, dengan berbagai fosforilasi protein lainnya Regulasi metabolisme sel selanjutnya dilakukan oleh sistem G-protein yang menghambat adenylyl cyclase © 2011 Pearson Education, Inc.

First messenger (memberi sinyal pada molekul seperti epinefrin) Figure 11.12 First messenger (memberi sinyal pada molekul seperti epinefrin) Adenylyl cyclase G protein Pasangan reseptor- G protein GTP ATP Second messenger cAMP Figure 11.12 cAMP as a second messenger in a G protein signaling pathway. Protein kinase A Respons seluler 41

Ion Calcium dan Inositol Triphosphate (IP3) Ion kalsium (Ca2+) bertindak sebagai second messenger dalam banyak pathways Kalsium merupakan second messenger penting karena sel dapat mengatur konsentrasinya © 2011 Pearson Education, Inc.

Endoplasmic reticulum (ER) Figure 11.13 EXTRACELLULAR FLUID Plasma membrane Ca2 pump ATP Mitochondrion Nucleus CYTOSOL Ca2 pump Figure 11.13 The maintenance of calcium ion concentrations in an animal cell. Endoplasmic reticulum (ER) Ca2 pump ATP Key High [Ca2 ] Low [Ca2 ] 43

Sinyal di relay oleh jaras transduksi sinyal akan memicu peningkatan kalsium dalam cytosol Jaras membuat pelepasan kalsium ikut dalam inositol triphosphate (IP3) dan diacylglycerol (DAG) sebagai second messengers tambahan Animation: Signal Transduction Pathways © 2011 Pearson Education, Inc.

Signaling molecule (first messenger) Figure 11.14-1 EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Figure 11.14 Calcium and IP3 in signaling pathways. Endoplasmic reticulum (ER) Ca2 CYTOSOL 45

Signaling molecule (first messenger) Figure 11.14-2 EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Figure 11.14 Calcium and IP3 in signaling pathways. Endoplasmic reticulum (ER) Ca2 Ca2 (second messenger) CYTOSOL 46

Signaling molecule (first messenger) Figure 11.14-3 CAIRAN EKSTRA SELULER Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Figure 11.14 Calcium and IP3 in signaling pathways. Various proteins activated Cellular responses Endoplasmic reticulum (ER) Ca2 Ca2 (second messenger) SITOSOL 47

Respon: Sinyal sel membuat pengaturan transkripsi atau aktivitas sitoplasmik Respon sel atas sinyal ekstraseluler kadang disebut “output response” © 2011 Pearson Education, Inc.

Respon Nuclear dan Sitoplasmik Jaras transduksi sinyal membuat regulasi satu atau lebih aktivitas seluler Respon dapat terjadi dalam sitoplasma atau dalam nukleus Banyak jaras sinyal mengatur sintesa ensim atau protein lain, biasanya dengan membalik gen on or off dalam nukleus Molekul yang diaktivasi final dalam memberi sinyal dalam jaras berfungsi sebagai faktor transkripsi © 2011 Pearson Education, Inc.

Inactive transcription factor Active transcription factor Figure 11.15 Growth factor Reception Receptor Phosphorylation cascade Transduction CYTOPLASM Inactive transcription factor Active transcription factor Figure 11.15 Nuclear responses to a signal: the activation of a specific gene by a growth factor. Response P DNA Gene NUCLEUS mRNA 50

Jaras lain mengatur aktivitas ensim lebih daripada sintesanya © 2011 Pearson Education, Inc.

Glucose 1-phosphate (108 molecules) Figure 11.16 Reception Binding of epinephrine to G protein-coupled receptor (1 molecule) Transduction Inactive G protein Active G protein (102 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (102) ATP Cyclic AMP (104) Inactive protein kinase A Active protein kinase A (104) Figure 11.16 Cytoplasmic response to a signal: the stimulation of glycogen breakdown by epinephrine. Inactive phosphorylase kinase Active phosphorylase kinase (105) Inactive glycogen phosphorylase Active glycogen phosphorylase (106) Response Glycogen Glucose 1-phosphate (108 molecules) 52

Signaling pathways juga dapat memengaruhi sebuah sel , misal perubahan bentuk sel © 2011 Pearson Education, Inc.

Wild type (with shmoos) Fus3 formin CONCLUSION Figure 11.17 RESULTS Wild type (with shmoos) Fus3 formin CONCLUSION 1 Mating factor activates receptor. Mating factor Shmoo projection forming G protein-coupled receptor Formin P Fus3 Actin subunit GTP P GDP 2 Phosphory- lation cascade G protein binds GTP and becomes activated. Formin Formin Figure 11.17 Inquiry: How do signals induce directional cell growth during mating in yeast? P 4 Fus3 phos- phorylates formin, activating it. Microfilament Fus3 Fus3 P 5 Formin initiates growth of microfilaments that form the shmoo projections. 3 Phosphorylation cascade activates Fus3, which moves to plasma membrane. 54

Wild type (with shmoos) Figure 11.17a Figure 11.17 Inquiry: How do signals induce directional cell growth during mating in yeast? Wild type (with shmoos) 55

Figure 11.17b Figure 11.17 Inquiry: How do signals induce directional cell growth during mating in yeast? Fus3 56

Figure 11.17c Figure 11.17 Inquiry: How do signals induce directional cell growth during mating in yeast? formin 57

Respon yang Fine-Tuning Ada empat aspek dari fine-tuning untuk dipertimbangkan Menguatkan sinyal (dan juga responnya) Spesifik pada respon Respon menyeluruh yang efisien , ditingkatkan oleh peningkatan protein Terminasi signal © 2011 Pearson Education, Inc.

Amplifikasi Signal Ensim cascades menguatkan respon sel Setiap langkah , jumlah produk yang diaktivasi lebih besar dari ketika langkah dimulai © 2011 Pearson Education, Inc.

Spesifitas Signaling Sel dan Koordinasi Respon Sel yang berbeda mempunyai koleksi protein Protein yang berbeda-beda ini memungkinkan sel mendeteksi dan merespon sinyal yang berbeda Sekalipun sinyalnya sama , dampaknya terhadap sel berbeda tergantung jenis protein dan pathways Cabang pathway dan “cross-talk” selanjutnya membantu sel koordinasi sinyal yang datang © 2011 Pearson Education, Inc.

Figure 11.18 Signaling molecule Receptor Relay molecules Activation or inhibition Figure 11.18 The specificity of cell signaling. Response 1 Response 2 Response 3 Response 4 Response 5 Cell A. Pathway leads to a single response. Cell B. Pathway branches, leading to two responses. Cell C. Cross-talk occurs between two pathways. Cell D. Different receptor leads to a different response. 61

Cell A. Pathway leads to a single response. Figure 11.18a Signaling molecule Receptor Relay molecules Figure 11.18 The specificity of cell signaling. Response 1 Response 2 Response 3 Cell A. Pathway leads to a single response. Cell B. Pathway branches, leading to two responses. 62

Activation or inhibition Figure 11.18b Activation or inhibition Figure 11.18 The specificity of cell signaling. Response 4 Response 5 Cell C. Cross-talk occurs between two pathways. Cell D. Different receptor leads to a different response. 63

Efisiensi Signaling : Scaffolding Proteins and Signaling Complexes Scaffolding proteins amerupakan protein relay besar dimana protein relay lainnya terlekat Scaffolding proteins dapat meningkatkan efisiensi transduksi signal denga mengelompokan bersama protein yang berbeda yang berperan sama pada jaras yang sama Pada beberapa kasus, scaffolding proteins juga membantu mengaktifkan beberapa protein relay © 2011 Pearson Education, Inc.

Three different protein kinases Figure 11.19 Signaling molecule Plasma membrane Receptor Three different protein kinases Figure 11.19 A scaffolding protein. Scaffolding protein 65

Terminasi Signal Mekanisme inaktivasi aspek essential dari cell signaling Jika konsentrasi ligand turun, akan diikat sedikit reseptor Unbound receptors dibalik menjadi status inaktif © 2011 Pearson Education, Inc.

Apoptosis integrasi sel multipel- jaras signaling Apoptosis diprogram atau mengendalikan sel bunuh diri Komponen dari sel dicokok dan di bungkus masuk vesikula yang didigesti oleh sel scavenger Apoptosis mencegah enzym dari leaking out of a dying cell dan sel tetangga yang rusak © 2011 Pearson Education, Inc.

2 m Figure 11.20 Figure 11.20 Apoptosis of a human white blood cell. 68

Apoptotic Pathways dan Signal yang Memicu mereka Caspases merupakan proteases (enzym yang memotong protein) yang membawa apoptosis Apoptosis dapat dipicu oleh Kematian ekstraseluler -signaling ligand Kerusakan DNA dalam nukleus Protein misfolding dalam retikulum endoplasmik retikulum © 2011 Pearson Education, Inc.

Apoptosis merupakan evolusi dini binatang dan utama bagi perkembangan dan pemeliharaan binatang Apoptosis mungkin menyertai beberapa penyakit seperti Parkinson dan Alzheimer ; interferensi dengan apoptosis berkontribusi dengan beberapa jenis kanker © 2011 Pearson Education, Inc.

Sel yg melakukan apoptosis Figure 11.22 Sel yg melakukan apoptosis ruang antar jejari 1 mm Jaringan Interdigital Figure 11.22 Effect of apoptosis during paw development in the mouse. 71

Jaringan Interdigital Figure 11.22a Jaringan Interdigital Figure 11.22 Effect of apoptosis during paw development in the mouse. 72

Sel membuat apoptosis Figure 11.22b Figure 11.22 Effect of apoptosis during paw development in the mouse. 73

Ruang antar jejari 1 mm Figure 11.22c Figure 11.22 Effect of apoptosis during paw development in the mouse. 74

Activation of cellular response Figure 11.UN01 1 Reception 2 Transduction 3 Response Receptor Activation of cellular response Relay molecules Figure 11.UN01 Summary figure, Concept 11.1 Signaling molecule 75

Figure 11.UN02 Figure 11.UN02 Appendix A: answer to Test Your Understanding, question 9 76