Signalling Pathways

Question 1

Cell Signalling

Answer 1

Part of a complex system of communications that governs basic cellular activities & coordinates cell actions

Question 2

Signal Transduction

Answer 2

any process by which a cell converts one kind of signal/stimuli into another

Question 3

Types of intracellular signalling

Answer 3

Autocrine, paracrine, endocrine

Question 4

Autocrine signalling

Answer 4

produced by a cell with a receptor on it

Question 5

Paracrine signallng

Answer 5

produced by a cell with a neighbouring receptor cell

Question 6

Endocrine signalling

Answer 6

cell signal that can be transferred to any cell with a receptor

Question 7

Molecular signalling pathways

Answer 7

Morphogens, notch-delta, RTK’s, transcription factors

Question 8

Two classes of proteins needed for communication

Answer 8

gap junctions, cell adhesion molecules

Question 9

Gap Junctions

Answer 9

connexon – transmembrane protein, 4 transmembrane domains, forms a hemichannel, when hemichannels align, material from cell to cell transfers

Question 10

Cell adhesion molecules

Answer 10

Cadherins & the immunoglobin superfamily – modify structure of cells by adhering material

Question 11

Morphogens

Answer 11

• Diffusible molecules such as growth factors that specify which cell type will be generated at a specific anatomic site & direct the migration of cells and their processes to their final destination
• Include: retinoic acid, transforming growth factor beta

Question 12

Retinoic Acid

Answer 12

• Small molecule, diffuses through the plasma membrane and binds to its receptor
• Acts to posteriorize the body
  o Anterior/posterior or anteroposterior axis of the embryo is crucial for determining the correct location for limbs & patterning of the nervous system
• Insufficient amounts will lead to a more anteriorized structure

Question 13

Transforming Growth Factor Beta/ BMP

Answer 13

• Members of the TGF-β superfamily include TGF-β, BMPs, activin, and nodal. These molecules contribute to the establishment of dorsoventral patterning, cell fate decisions, and formation of specific organs, including the nervous system, kidneys, skeleton, and blood. We have 3 TGF-B isoforms: TGF-B1, -B2, -B3

Question 14

Sonic Hedgehog Gene (SHH)

Answer 14

• SHH was the first mammalian ortholog of the drosophila hedgehog gene (Hh) to be identified
• SHH is a secreted morphogen critical to early patterning, cell migration, differentiation

Question 15

Primary receptor for SHH

Answer 15

Patched (PTCH), a 12-transmembrane domain protein that, in the absence of Shh, inhibits Smoothened (Smo), a seven-transmembrane domain G protein-linked protein, and downstream signaling to the nucleus. If smo is inhibited, a complex with cos2 and fu phosphorylates and cleaves gli to make it a transcriptional repressor

Question 16

What occurs in the presence of SHH

Answer 16

Ptc inhibition is blocked and downstream events follow, including nuclear translocation of Gli (Gli1, Gli2, Gli3), with transcriptional activation of target genes, such as Ptc-1, Engrailed, and others

• Shh is cleaved, cholersterol added to its N-terminus, making the shh hydrophobic. The modified shh ligand inhibits the receptor, permitting smo signalling which acts on cos2, fu, and sufu which no longer reacts with gli. Activated gli translocates to the nucleus to activate target genes with cAMP binding protein (cBP)
• Sensory and motor neurons are determined by the concentration of morphogens (shh)

Question 17

WNT/B-Catenin pathway

Answer 17

• Specific WNTS bind to one of the 10 frizzled (FZD) 7-transmembrane cell surface receptors and bind with low-density lipo-protein receptor-related-proteins (LPR5/6) coreceptors, thereby activating downstream intracellular signalling events

Question 18

What occurs in the absence of WNT

Answer 18

B-catenin is phosphorylated by a multi protein complex and targeted for degradation. Target gene expression is repressed by T-cell factor (TCF)

Question 19

What occurs in the presence of WNT

Answer 19

WNT binds to FZD receptor, LRP coreceptors, DVL is phosphorylated so it can’t activate GSK-3 and B-catenin is not phosphorylated – accumulates in the cytoplasm, some enters the nucleus to activate target gene transcription

Question 20

Notch-Delta Pathway

Answer 20

• Notch signalling pathway specifies which cel fate precursor cells will adopt
• Integral for cell fate determination, maintenance of stem cell niches, proliferation, apoptosis and differentiation
• Ligand-receptor binding triggers proteolytic events, some are mediated by secretases, leading to the release of the notch intracellular domain (NICD).

Question 21

Transcription factors

Answer 21

• Belong to a large class of proteins that regulate the expression of target genes via. activation/repression mechanisms

Question 22

Receptor tyrosine kinases (RTKs).

Answer 22

• Many growth factors signal by binding to and activating membrane-bound RTKs.
• Essential for the regulation of cellular proliferation, apoptosis, and migration as well as processes such as the growth of new blood vessels and axonal processes in the nervous system

Question 23

Two types of kinases

Answer 23

Tyrosine and serine-threonine

Question 24

Vitamin A abnormal function/mutations

Answer 24

The central nervous system (hydrocephalus, spina bifida), eyes (anophthalmia, microphthalmia), face (harelip, cleft palate), dentition, ear (accessory ears, otosclerosis) limb, urinogenital system (cryptorchidism, ectopic ovaries, pseudohermaphrotisism, renal defects), skin (subcutaneous cysts), lungs (hypoplasia), and heart (incomplete ventricular septation, spongy myocardium, aortic arch defects, aorticopulmonary septal defects, valvulus communis)*.

Question 25

TGF- beta family abnormal functions/mutations

Answer 25

Affects nervous system, kidneys, skeleton and blood

Question 26

Hedgehog abnormal functions/mutations

Answer 26

Brain defect: holoprosencephaly, Smith-Lemli-OPitz Syndrome, Grig’s and Pallister Syndrome and Gorlin’s Syndrome

Question 27

What happens when NICD translocates to the nucleus

Answer 27

intracellular events induce the expression of an HLH transcription factor that maintains the progenitor state by repressing pro-neural basic HLH genes

Question 28

HES

Answer 28

Hair enhancer of split