BioE 002 Lecture Notes 21 4/21/25

Activated Receptor Tyrosine Kinases

Needs ATP

Ras genes

According to the NCI, drives over 30% of all human cancers

Activated by Tyrosine Kinase Receptors

• PI-3 Kinase pathway

• JAK-STAT pathway

Different pathways based on their receptors

Pathway A and Pathway B

Pathway A

Activation of transcription factors such as CREB

Pathway B

Contains serine-threonine kinase, which directly phosphorylates and activates a member of the Smad class

Some ion channels

Controlled by electrical currents instead of ligands and are called voltage0gated ion channels. Ligand binds to a channel and opens it by changing conformation.

Signal Transduction

Is a multi step process

Cytokinesis

Broad category of small proteins (~5 - ~25 kDa) important in cell signaling. They are peptides and can’t cross the lipid bilayer

Examples:
Chemokines

• Interferons

• Interleukins

• Lymphokines

• Tumor necrosis factors

• Transforming growth fator

Cell signaling

Can lead to the regulation of the activity of proteins. After the response, the signal is terminated. A process by which cells communicate

Cell signaling amplification

Occurs in small steps. Process where a small initial signal is transformed into a larger, more powerful response within a cell.

Autocrine

Type of signaling where the cell that expresses the messenger molecule also produces the receptors for that messenger

Hormones

AKA endocrine messengers

Conformation

Protein kinases and phosphates act by altering _________ of the signaling proteins

Cell adhesion

Process by which extracellular messages translate into a cascade of intracellular changes

G-protein couple receptors

Contains 7 transmembrane alpha helices

Cyclic AMP

Signal molecule not used for extracellular signaling

False

In endocrine signaling, the signal molecules act on the target cell only in close proximity

First messenger

A hormone or ligand can be considered as a ______________

Receptor Tyrosine Kinases

Family of receptors that mediates the biologic actions of a wide variety of ligands, including insulin, and other growth factors

Dimerization

Occurs when a ligand binds to the receptor tyrosine kinase

Cells with low cell division

• Nerve cells

• Muscle cells

• Red blood cells

Cells with inducible cell division

• Liver cells

• Lymphocytes

Cells with high cell division

Hematopoietic stem cells. Has asymetric cell division

Stem cells

Precursors to all kinds of cells

Quiescent cells (G₀)

Terminally differentiated and lost the ability to receive signals to initiate division.

Gap Stage 1

The initial stage of the cell cycle, where the cell grows, increases its organelles, and prepares for DNA replication

Synthesis

Where DNA replication occurs, creating a complete copy of the genetic material

Gap Stage 2

A period in the cell cycle where the cell continues to grow and prepare for cell division

Mitosis

Cells divide

Prophase

Chromosomes condense, nuclear envelope breaks down by retracting into the ER, spindle poles duplicate, microtubules form the mitotic spindle apparatus, and kinetochore assembles.

Prometaphase

Spindle microtubules from each pole attach to chromosome kinetochores and center sister chromatid pairs in the spindle.

Metaphase

Chromosomes align at the metaphase plate.

Anaphase

Spindle microtubule shortening and microtubule-based motors pull each sister chromatid toward an opposite spindle pole

Telophase

Chromosomes decondense, and each presumptive daughter cell reassembles a nuclear membrane around its chromosomes.

Cytokinesis

Cell division into two separate daughter cells. Contractile ring (actin and myosin) forms the cleavage furrow to split the cell.

Centrosome

A cellular structure involved in cell division that produces microtubules.

Before cell division, it duplicates and then, as the division begins, the 2 centrosomes move to opposite ends of the cell.

Microtubules

Assemble into a spindle between 2 centrosomes and helps separate the 2 identical sister cells

Kinetochore

A multilayer protein structure located at or near the centromere of each mitotic chromosome from which microtubules
extend toward the spindle poles of the cell; plays an active role in movement of chromosomes toward the poles during anaphase.

Cylin-dependent kinase activation

Initiates centrosome splicing during mitosis

Interphase

Chromosome/centrosome duplication and cohesion

Types of microtubules

• Astral MTs

• Kinetochore MTs

• Polar MTs

Astral Microtubules

Extends from the centrosome to the cell cortex during cell division, forming part of the mitotic spindle

Kinetochore Microtubules

Connected to the chromosomes

Polar Microtubules

Originates from opposite poles in the cell and overlaps in the middle of the spindle apparatus

Cell cycle model organisms

• Saccharomyces cerevisiae

• Schizosaccharomyces pombe

• Xenopus laevis

• Drosophilia melanogaster

• Human tissue culture cells

At the checkpoint

The cell makes decisions to enter the next phase

• Performs replicating organelles in preparation for M phase. Monitors to see if it works before entering the next phase

• Cells monitor the fidelity of the various processes required for cell division

• This system is deeply conserved in eukaryotes

Cell cycle checkpoints

• Cyclin-dependent kinases require association with other proteins (cyclins(

  • Multiple biochemical mechanisms ensure that the CDKs are active only in the stages that they need to be

Mechanisms involved in regulating CDKs

• Cyclin binding

• CDK phosphorylation state

• CDK inhibitors

• Controlled proteolysis

• Subcellular localization

Cyclin A

Forms an activating complex with CDK2 in S phase with CDK1

Cyclin B

Only forms a complex with CDK1

Phosphatase Cdc25

Activates when DNA replication is done

Activation of Mitotic CDKs

Promotes mitosis and the breakdown of lamins

CDK1

Triggers chromosome condensation by initiating phosphorylation events on key proteins.