Topic 14-11 14 Cell Signaling. Topic 14-12 Focus on higher order vertebrates Multiple levels of cell signaling Endocrine Cells producing signaling factors.

Topic 14-1 1

14 Cell Signaling

Topic 14-1 2

Focus on higher order vertebratesMultiple levels of cell signaling

EndocrineCells producing signaling factors are physically separatedMessenger molecules are secretedCarried in blood or extra-cellular fluidTarget Cells

Membrane receptorsIntracellular actions via signal cascade

Cytoplasmic receptorsUsually a specific transport system to move signal molecule-receptor complex to nucleus – response element

Cell Signaling

Topic 14-1 3

Multiple levels of cell signalingParacrine

Features most similar to endocrine signaling

Major differenceTarget cell found in the same tissue

Messenger molecules carried across extra-cellular matrix or through extra-cellular fluid

Many growth factors are associated with the matrix

AutocrineCellular self-signaling

Cell Signaling

Topic 14-1 4

Multiple levels of cell signalingCell Signaling

Topic 14-1 5

Multiple levels of cell signalingAdhesion

Cell to cell interactionCells identify cell-types nearby

Cell to extra-cellular matrix interactionCells identify their physical environment

Cell Signaling

Topic 14-1 6

Forms of signaling molecules

GassesNO

CO

Steroid HormonesTestosterone

Estradiol

Progesterone

GlucocorticoidsCortisol

MineralocorticoidsAldosterone

Cell Signaling

Topic 14-1 7

Forms of signaling moleculesNeurotransmitters

Cell Signaling

Topic 14-1 8

Forms of signaling molecules

Peptide Hormones and Growth Factors

Cell Signaling

Topic 14-1 9

Forms of receptorsSteroid receptors

Present in the cytoplasm or localized in the nucleusRecall Glucocorticoid receptor – interaction with the GRE

Cell Signaling

Topic 14-1 10

Forms of receptorG protein-coupled receptors

Seven transmembrane helix familyProgesterone R

-adrenoceptors

Cell Signaling

Topic 14-1 11

Cell Signaling

The 2 adrenoceptor

- S- S-

Extracellular

domain

Intracellulardomain

Transmembrane domain

Topic 14-1 12

Forms of receptorsTyrosine Kinase Receptors

Not only a receptorAlso an enzyme

Tyrosine kinase

ExamplesInsulin RIGF Type 1 REGF

Cell Signaling

Topic 14-1 13

Forms of receptorsCytokine superfamily receptors

No catalytic domain

Interact with nonreceptor protein-tyrosine kinases

Src family

JAK family

Cell Signaling

Topic 14-1 14

Bla

nk

Bla

nk

The Insulin Receptor Cascades

IR is a receptor tyrosine kinase

A family of receptors involved in cell growth and differentiation

TetramerTwo and two subunits

Cell Signaling

Topic 14-1 15

Bla

nk

Bla

nk

The Insulin Receptor CascadesAbsence of insulin – tyrosine kinanse is inactiveBinding causes a conformational changeActivated tyrosine kinase transfers phosphate groups to:

Specific tyrosines of alternate subunit autophosphorylationA soluble protein substrate (family) – insulin receptor substrates (IRSs)

Cell Signaling

Topic 14-1 16

The Insulin Receptor Cascades Insulin receptor substrates (IRSs)

Phosphorylated IRS – a single function – to activate downstream messengers

Like several other signaling proteins contains an SH2 domain

SH2 domains have high affinity for phosphorylated tyrosines

Possession of these SH2 modules allows proteins in a signal cascade to be strung together

Different cells contain different protein messengers with SH2 domains

Insulin signaling varies in effect depending on cell type

Cell Signaling

Topic 14-1 17

The Insulin Receptor Cascades Insulin receptor substrates (IRSs)

Insulin may signal along several independent pathways

One of these is phosphatidylinositol-3-hydroxy kinase (PI3K)

Cell Signaling

Topic 14-1 18

Blan

k

Cell SignalingThe Insulin Receptor Cascades

Phosphatidylinositol-3-hydroxy kinase (PI3K)

Catalyses phosphate addition to the 3’ position on the sugar ring of phosphatidyl inositolProducts:

PI 3,4-biphosphate (PIP2)PI 3,4,5-triphosphate (PIP3)Remain in the cytosolic leaflet of lipid bilayerMembrane-bound lipid messengers

Diverse functions in many cell types

Activation of protein kinase B via its PH domain

Topic 14-1 19

Cell SignalingThe Insulin Receptor Cascades

Phosphatidylinositol-3-hydroxy kinase (PI3K)

Topic 14-1 20

Cell SignalingThe Insulin Receptor Cascades

Protein kinase BPIP2 recruits PKB to plasma membrane

Binding – conformational changeTransfer of glucose transporters to the plasma membrane

Increased protein synthesis

Glycogen synthase

Glucose to glycogen

Topic 14-1 21

The Insulin Receptor Cascades Insulin receptor substrates (IRSs)

Insulin may signal along several independent pathways

Another IRS pathway: Ras – cell growth and proliferation

Cell Signaling

Topic 14-1 22

The Insulin Receptor Cascades Ras

ras gene - originally discovered as a viral oncogene

Also part of the normal genome

Many tumor cells contain a mutant ras

Protein product RasSmall G-protein

At inner surface of plasma membrane

Lipid group embedded in inner leaflet

Cell Signaling