G-protein coupled receptors 7-pass transmemb proteins

GPCRs: largest fam cell surface receptors (>700 in humans), wide variety sig mlcs can activate GPCRs 50% known drugs work thru GPCRs activate G proteins

intrinsic GTPase activity of Gα

subunit contributes to switch off

signaling

Each G protein activated by specific set receptors, activates particular set downstream targets. 20 types

mammal G proteins

Adenylyl cyclases & mPLCs: most frequent targets G proteins. Production cAMP rapid, dramatic: 20 fold 20 sec

cell response depends

transcriptional regulators in

cell

inositol phospholipid pathway

protein kinase C phosph set of intracell proteins varies depending cell type

Active RTKs inactivated 2 ways: protein tyrosine phosphatases remove phosphates/ Endocytosis remove active receptors from cell surface

Receptor tyrosine kinases (RTKs)

Enz-coupled receptors

Cell responses mediated by phospholipase C activation Signal mlc target tissue major response Vasopressin (peptide hormone) liver: glycogen breakdown Acetyocholine: pancrease: secretion amylase (digestive enz) Acetylcholine: smooth musc: contraction Thrombin (proteolytic enz): blood platelets: aggregration

Most RTKs activate monomeric GTPase Ras

(Ras GEF) GEF - Guanine Exchange Factor

Ras activates MAP kinase signal module

Cell responses mediated cyclic AMP extracell signal mlc: target tissue:

major response adrenaline: heart: ^ HR & force contraction Adrenaline: skel musc: glycogen breakdown Adrenaline,

ACTH, glucagon: fat, fat breakdown ACTH: adrenal gland, cortisol secretion

MAP kinase = mitogen activated PK. Mitogens: sig stim cell prolifer

stim cell proliferation, survival, or differentiation,Depend cell & other signals

Receptor tyrosine kinases (RTKs)

RTKs can promote cell survival thru PI3 kinase

PI 3-kinase = phosphoinositide 3-kinase

RTKs can activate PI-3-kinase-Akt pathway

Apoptosis = programmed cell death

Activate Akt promotes cell survival

US 2007, >200,000 women diagnosed BC. 40,500 died. Mutation: overexpression of RTK

HER2: ~30% BC. strongly assoc ^ disease recurrence & worse prognosis. Treatment:

monoclonal antibody trastuzumab (Herceptin) that targets HER2

HER2 dimerizes promiscuously w other fam members w/o ligand binding. High levels

HER2 sensitize cells to even low levels growth factors: excessive cell growth

HER2 1 of fam RTKs respond to variety growth factors: promotes

cell proliferation, opposes apoptosis, must be tightly reg to prevent uncontrolled cell growth

activated subunit & activated complex can signal to downstream targets. 2 most frequent targets enzymes G proteins: adenylyl cyclase, phopholipase C. Activated adenylyl cyclase catalyzes formation of 2nd messenger cAMP. cAMP can activate # different responses depending on cell type. cAMP commonly activates cyclic-AMP-dependent protein kinase (PKA: glycogen breakdown & activation of gene expression) G proteins can activate phospholipase C, cleaves inositol phospholipid to generate inositol 1,4,5 triphosphate (IP3) & diacylglycerol (DAG). IP3 opens Ca channels in ER, ^ cytoplasmic Ca levels. DAG, w Ca, activates PKC, can Phosph variety downstream targets. Most common enz-coupled receptors: receptor tyrosine kinases: single a-helical region spans PM. on binding signal, RTKs dimerize, activation tyrosine kinase activity, Phosph # sites cytoplasmic domains serve as BS other intracell signaling proteins. RTKs commonly active GTP-binding protein Ras, activates MAP kinase module. RTKs can activate PI 3-kinase, activation Akt. Akt Phosph Bad, inhib Bad binding Bcl2. Unbound Bcl2 inhib apoptosis. RTK sign thru Akt required for cell survival

Sig pathways can be highly interconn

cutcut-paste

(transplantation)

devel genetics = study of mutants

gene disrupted by mutation required for development of fly body plan

normal gene

normal fly fly w abnormal phenotype

similar mech promote devel of all animals

experimental embryology

single cell to org

Study devel bio: Embryology, metamorphosis, juvenile growth, adult growth, wound healing, tissue homeostasis, reproductionDescriptive embryology. intellectual curiosity. medical relevance: in vitro fertilization, cancer bio, birth defects, wound repair, potential for regeneration agricultural relevance: Max yield, in vitro fertilization, cloning animals. descriptive & experimental embryology, devel genetics

studying diverse animals: fundamental mech & mlcs drive devel all animals highly conserved. ½ genes each animal MO in humans, similar funct both species. Fertilization, egg & sperm unite: gen unique diploid individ, fusion haploid nuclei to form diploid zygote. initiate embryogenesis by activating egg. egg & sperm formed by meiosis, gen 4 haploid gametes from single diploid germ cell. Cleavage newly formed embryo many rounds of cell division w/o growth. M follows S w/o intervening G1 & G2. Cleaving cells: blastomeres. End cleavage blastula: large # cells hollow ball cells. (organization of embryos vary) Gastrulation, cells blastula dramatic reorganization: Each germ layer rise unique subsets cell types in embryo. Neurulation, all vert, not invert, forms NS. spec region of ectoderm, neural plate, folds along dorsal midline, separates rest ectoderm to form neural tube, precursor CNS, neural crest, rise # other tissues ie peripheral NS Organogenesis ∆ cell behavior basis devel: cell proliferation, specialization (differentiation), cell movement, cell interaction. makes cell diff? Differential gene express all cells same DNA seq, diff cell types express diff genes, diff protein compositions, cell organization, behaviors cells become diff organized & reprod way: Regional specification/axis formation embryos determine which cells rise head, tail (anterior/posterior axis) back, belly (dorsal/ventral axis) left right (left/right axis). cells organize into tissues & organs: Morphogenesis precise shapes & sizes parts body. Gastrulation, neurulation, organogenesis all morphogenetic. similar cells organize into diff shapes & patterns? Pattern formation many diff events: precise placement body parts resp 1 another. axis formation, proper placement, organization limb etc reproducible patterns of feathers on a bird, hairs on mouse or spots on butterfly wing cells maintain tissues & organs? Stem cells hottest devel bio. potential of cells for med applications.

up to 50% of the genes in worms, flies, or fish are also present in humans, carry up to 50% of the genes in worms, flies, or fish are also present in humans, carry out similar functionsout similar functions

Fertilization

GastrulationCleavage Neurulation

Organogenesis

embryonic development: embryonic development: embryogenesisembryogenesis

2n = 46

fertilization

meiosis

2n 46 chromosomes

2n 46 chromosomes

FertilizationFertilization 1. Creates a unique diploid individual

2. Initiates embryogenesis by activating the egg

cleavage cell division w/o cell growth. Cleaving cells: blastomeres end of cleavage, embryo: blastula

M phaseDNA

segregation & cell division

S phaseDNA replication

No G1

No G2

Gastrulation: dramatic reorganization cells

Germ cells set aside early in devel, do not arise from any particular germ layer

What mech drive embryogenesis? devel driven by cell behaviors

neurulation (only vert)

gastrulation creates 3 germ layers

Organogenesis: formation internal organs (kidney, lung, liver etc.) Limbs (fins, arms, legs) Sensory organs (eyes, ears)

What makes cells diff? 411 cell types in humans: nerve cells, RBC, smooth musc, fat (adipose), intestinal epithelial, striated muscle, bone tissue w osteocytes, loose connective tissue w fibroblasts