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Specialized cell signaling pathways 2
Dr. Tania A. Shakoori
The Hedgehog Pathway
Holoprosencephaly (HPE)
Basal Cell Carcinoma
Medulloblastoma
What’s common?
• All result from errors of Hedgehog Signaling Pathway
• key regulator of embryonic development• 3 Hedgehog homologues– DHH (desert HH)– IHH (indian HH)– SHH Sonic (SHH) is the best studied
Major Steps
• Hh ligand precursor Hh ligand (multimeric)• released with help of ‘dispatched’ (disp)• Binds to ‘patched’ (ptch) on receiving cell• Releases smoothened (Smoh) from
constitutive inhibition• Activation of Gli2/3 complex activation of
Gli1 gene transcription
Significance
• It plays a key role in regulating organogenesis, such as in the growth of digits on limbs and organization of the brain.
• Sonic hedgehog is the best established example of a morphogen as defined by Lewis Wolpert's French flag model—a molecule that diffuses to form a concentration gradient and has different effects on the cells of the developing embryo depending on its concentration.
• SHH remains important in the adult. It controls cell division of adult stem cells and has been implicated in the development of some cancers.
video
• Please Copy paste the following link to get to the video:
• https://drive.google.com/file/d/0B8lwCh5HN0GTeURlOXpuMW9BM2c/view?usp=sharing
Sonic says: True or false
• Hh is released with help of ptch?• Hh attaches to the receiving cell via disp?• Transcription is activated in Hh pathway by
‘Gli’ transcription factors?• It maybe involved in holoprosencephaly? • In Tumor micro environment Hh secretion is
most likely to be inhibited?
Wnt Pathwaywingless + Int
Dr Tania Shakoori
Wnt pathways
• Types– canonical Wnt pathway– noncanonical planar cell polarity pathway– noncanonical Wnt/calcium pathway
The Canonical Pathway
Role of Wnt ligand
• The canonical Wnt pathway (or Wnt/β-catenin pathway) is the Wnt pathway that causes an accumulation of β-catenin in the cytoplasm and its eventual translocation into the nucleus to act as a transcriptional coactivator of transcription factors that belong to the TCF/LEF family.
• Without Wnt signaling, the β-catenin would not accumulate in the cytoplasm since a destruction complex would normally degrade it.• This destruction complex includes the following proteins: • (Axin, adenomatosis polyposis coli (APC), protein phosphatase
2A (PP2A), glycogen synthase kinase 3(GSK3) and casein kinase 1α (CK1α).
• targeting it for ubiquitination proteasomedigested.
With Wnt ligand
• Wnt binds Fz and a co receptor (LRP5/6) the destruction complex function becomes disrupted.
• translocation of protein Axin, and the destruction complex to the plasma membrane.
• Axin becomes de-phosphorylated and its stability and levels are decreased.
• Dsh then becomes activated and it inhibit the activity of the destruction complex.
• This allows β-catenin to accumulate and localize to the nucleus and subsequently induce a cellular response via gene transduction alongside other transcription factors.
THINK!!
• What would happen if one of the proteins of the destruction complex was mutated and not functional???
Roles of the 3 pathways
• The canonical Wnt pathway gene transcription• the noncanonical planar cell polarity pathway regulates the cytoskeleton that is responsible for the shape of the cell
• the noncanonical Wnt/calcium pathwayregulates calcium inside the cell
significance
• Carcinogenesis/tumors– breast and prostate cancer, glioblastoma,
• Other diseases:– type II diabetes, (role in insulin sensitivity!) and
others• Embryogenesis
Review video
• Just copy paste the following link to get to the video:
• https://drive.google.com/file/d/0B8lwCh5HN0GTYm9renh1NzJUdHc/view?usp=sharing