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