Cellular Signaling (Week 10)

Ligand-receptor, receptor, cascade, response

4 critical steps involved in every cell signaling pathway

1. __-__

2. __ changes

3. Intracellular __

4. Cellular __ → Eventually Desensitization/Adaptation

Extra, ligands, receptor, signal transduction

• Receptors (proteins) receive signals (ligands) __cellularly

• __ can be proteins or hydrophobic

• __ locations - Transmembrane or intracellular

• __ __ pathways: Convert signals into appropriate responses

Enzymes, transcription, cytoskeletal, channels

Effector proteins (4)

__, __ factors, __ proteins, __

Metabolic, gene, shape/movement, ion

Cellular responses

__ changes, __ expression, cell __/__, __ concentrations

Autocrine

Signal released from same cell containing receptor (cell-cell signaling)

Juxtracrine

Contact-dependent between adjacent cells, using cell surface ligand bound to cell surface receptor (cell-cell signaling)

Paracrine

Released from cell to nearby cells (cell-cell signaling)

Endocrine

Hormones released from specialized cells, travel thru bloodstream to distant targets (cell-cell signaling)

Development, growth, gap, nitric oxide, cytokines, hormones

Cell-Cell Signaling Examples

• Autocrine - for __ and __

• Juxtracrine - __ junctions

• Paracrine - __ __ (gas), __

• Endocrine - __

Peptide, surface

__ hormones bind to cell __ receptors

• Ex: Insulin, glucagon, pituitary hormones

Steroid, cytosolic, transcription

__ hormones diffuse across cell membrane and bind to __  receptors

• Act as __ factors in nucleus

• Ex: Testosterone, estrogen, corticosteroids, glucocorticoids

Nitric oxide, hydrophobic, dilation, relaxation

Diffuse across cell membrane (__phobic) and alter enzyme activity — signal molecule type

• Ex: Nitroglycerin for angina, viagra for erectile dysfunction

• Cell response is vaso__ and smooth muscle __

Neurotransmitters

Small hydrophilic molecules via paracrine communication

Growth factors

Stimulate and control growth and proliferation

Eicosanoids

Lipid molecules used in autocrine and paracrine signaling

False

If you inject a lipid insoluble ligand to cells intracellularly, there will be a consequential cellular response (T/F)

Heterotrimeric, alpha, betta, gamma

G proteins are __ic → 3 subunits = __, __, __

alpha

G protein __ subunit separates and activates adenyl cyclase

ATP, cAMP, PKA

In Gs

AC converts __ → __ → activates PKA

IP3

Gq 2nd messengers from PIP2

• __: Opens Ca2+ channels in SR → increased Ca2+ intracellularly → binds to calmodulin → activates PK → cell response

DAG

Gq 2nd messengers from PIP2

• __: Activates PKC → cell response

Hydrolysis, phosphodiesterase, phosphatases

3 ways to stop G protein pathways

• Inherent GTPase __ to stop G protein

• cAMP __ (enzyme) to stop 2nd messenger

• __ (enzyme) to de-phosphorylate target proteins

Receptor Tyrosine Kinases (RTKs)

Regulation of cell growth, differentiation, and survival

RTKs, dimerize, residues, target

Receptor Tyrosine Kinases

• Ligand binding leads to __s (stacks of Tyrosine) to __

• Activates kinase activity and phosphorylation of tyrosine __

• Phosphorylated tyrosines bind to target __ → activate additional signaling pathways

GDP, GTP

In RTK and MAP Kinase pathway

• GEF converts Ras-__ to Ras-__

Non-Tyrosine Kinase Receptors

Commonly used by cytokine signaling and some peptide hormones

Kinase, dimerization, intracellular

Non-Tyrosine Kinase Receptors

• Cytoplasmic domain has NO __ activity

• Receptor __ → Cross-phosphorylates other tyrosine kinase enzyme

• These then phosphorylate __ domain on receptor → receptor binds to target protein and activate cascade

Cytokines, tyrosines, STATs, nucleus

JAK-STAT Pathway

• __ induce dimerization of receptors

• Phosphorylated __ by JAKs and later phosphorylated __ by JAKs

• P-STAT proteins dimerize and translocate to __

• Transcription factors

Development, patched, smoothened, Gli

Hedgehog pathway - For early stages of __

• No hedgehog protein → __ protein inhibits__ protein

• In Active: Take away patched → Hedgehog proteins bind to patched receptor → activate __ complex (transc. factor)

Notch, delta, protease, secretase, transcription

Notch pathway

• __ is a transmembrane protein receptor for Delta (ligand)

• __ binds to notch

  • __ 1st cleavage → gamma-__ 2nd cleavage to Notch domain

  • Translocate to nucleus and act as __ factor

genetic defects, JNK1

Neurodegenerative diseases are mostly a result of down-regulation of cell signaling → __ __ to proteins

• Ex: __ (Receptor) is downregulated in Alzheimer’s disease

Gleevac, tyrosine kinase

Pharmacotherapies for cell signaling

• __ blocks ATP binding site of __ __

• Without ATP there is no phosphorylation of blood cancer cells

Tofacitinib, JAK kinase, gut

Pharmacotherapies for cell signaling

• __ competes with ATP binding site to __ __, inhibit STAT activation and gene transcription

  • less activation of immune response with __ inflammation (i.e. ulcerative colitis)

Trastuzunab, EGFR, F2

Pharmacotherapies for cell signaling

• __ controls overexpression of __

• Uses an antibody (__ receptor) to directly bind to HER2 receptor

  • Inhibits tumor cell proliferation (breast cancer)