Chapter 17 & 18 Cell Signaling

what are the types of cell signaling

Direct Cell-Cell contact and signaling by secreted molecules

Direct Cell-Cell contact

known as Juxtacrine, is membrane bound and does not involve secreted molecules

Signaling by secreted molecules

distance over which signal is transmitted, known as endocrine (long distance)- hormones in the blood such as insulin and adrenaline

Paracrin (neighboring cells)- local mediators such as growth factors and immune signaling

• neural signaling- actelycholine and dopamine which

autocrine (signaling and target cell is the same)- releases molecules that bind to its own receptors

Stages of cell signaling

Signal Reception, signal transduction, and the cellular response

Signal Reception

consists of a ligand binding to a receptor. The receptor types include

• intracellular receptors

  • Cell Surface receptors

Intracellular receptors

They are hydrophobic

non polar

only interact with steroid hormones

Cell Surface receptors

Hydrophilic ligands

polar

Signal Transduction

Relays a signal or multiple signals inside the cell

Cellular Receptors

Changes in gene expression, metabolism, or cell shape

• Activation of enzymes (glycogen breakdown)

• opening ion channels

• cytoskeletal changes (cell movement)

Types of molecules

Ligand (primary messengers)

Receptor Proteins

Effector Proteins

Intracellular signaling molecule

Second Messengers

Ligand (primary messengers)

Includes hormones, neurotransmitters, lipids, proteins by binding to target cells to induce conformational change

physical stimuli includes Light (photons) and mechanical force

Receptor Proteins

Includes Intracellular proteins that are hydrophobic molecules such as steroids, NO, gunaylyl cyclase

Includes Cell surface proteins that are hydrophilic and polar such as ion-channel coupled receptors, G-protein coupled receptors (GPCRs), and Enzyme coupled receptors.

Intracellular Signaling Proteins

Includes enzymes such as: Kinases, phosphatases, proteases, adenylyl cyclase

• molecular switches includes:

  • G-Proteins (active when bound to GTP, inactive with GDP)

  • Phosphorylation-based switches (protein kinases and phosphatases)

Second Messengers

They are small NON_PROTEIN molecules that AMPLIFY signals

these include:

• cAMP (from ATP by adenylyl Cyclase)

• cGMP (from GTP by Guanylyl Cyclase)

• DAG and IP3 (From membrane lipids by phospholipase C)

• Ca2++ ions (released from ER for signaling)

Effector Proteins

They are the final targets of signaling

includes:

• Enzymes (glycogen phosphorylase- breaks down glycogen)

• Transcription Factors ( CREB- regulates gene expression)

• Cytoskeletal Proteins (actin, Arp2/4- involved in cell movement)

Signal Transduction Pathway

Signal Relay- signal is transmitted through molecules inside the cell

Amplification- one activated molecule can activate many others

Integration- Different pathways interact and influence each other

Feedback- the cell can regulate the intensity of the signal

Characteristics of Cell Signaling

Specificity- the ligand triggers different responses in different cell types

Integration and Coordination- multiple pathways interact with eachother

Dynamics (speed & duration)- Fast responses changes existing proteins (Ion channgels, enzyme activation), Slow response changes in gene expression (transcription factors activation)

Signal Detection- (turning off signals)

• receptor sequestration (inactivation via endocytosis)

• receptor down regulation

• receptor inactivation

• signaling molecule degradation

Sensitivity- Even small amounts of ligans can cause large responses

Intracellular Receptors

hydrophobic ligands such as steroids, thyroid hormones, that are located in the cytoplasm or nucleus and diffuse through membranes, bind to receptors, then receptor-ligand complexes, and then gene expression

• change in cell behavior is change in gene expression

• activates gunaylyl cyclase which increases cyclic GMP

Intracellular Enzymes

change in behavior causes a change in muscle cell relaxation- ex vasodilation

Ligand-gated ion channels

they are nuerotransmitters and are small hydrophilic molecules. they are located on the cell surface of the plasma membrane. They open and close a channel by ligand binding

• change in cell behavior changes the inion flux across membranes

  • depolarization

  • hyperpolarization

G Protein coupled receptors (GPCR)

Largest family of cell-surface receptors (7 transmembrane domain proteins),

• Extracellular domain- ligand binding domain

• Intracellular domain- heterotrimeric G Protein

G- Protein Activation Pathway

GPCR binds to a ligand, which then activates heterotrimeric G-Proteins ( alpha, beta, gamma). This then casues alpha subunit to be exchanged from GDP to GTP and dissociates from beta-gamma, both subunits then activate downstream targets.

G Protein inactivation

alpha hydrolyzes GTP to GDP (helped by RGS proteins), the subunits then reassemble

GPCR Effector Proteins

Adenylyl Cyclase activates cyclic amp (cAMP) where atp is converted ATP

phospholipase C- activates DAG plus IP3- PIP2 is cleaved

Enzyme linked receptors

Ligands that promote growth factors and insulin. Its structure includes a single-span transmembrane protein and consists of two domains, intracellular and extracellular domains.

• intracellular domains consists of

  • Intrinsic enzymatic activity- receptor tyrosine kinase (RTK- largest family)

  • forms complex with non receptor tyrosine kinase

Receptor Tyrosine Kinas (RTKs)

when ligand binding to receptor triggers dimerization and autophosphorylation in the intracellular domain

• this causes phosphorylatio- new binding sites for signaling proteins with SH2 domain

• it is a kinase that targets map Kinase (there are 3, MAPK [erk'], MPKK [mek], MAPKKK [raf] )

RTK pathway

RTK activates adaptor proteins Grb2 which then activates SOS which activates Ras (Gtp-bound)

Ras-Gtp activates Raf (MAPKKK) which activates Mek (MAPKK) which activates ERK (MAPK)

Erk enters the nucleus which phosphorylates TFs (Myc and Fos)