Exam 4 - TGFβ/Gunanylyl Cyclase R/NO&Ion CLRP Flashcards

1
Q

TGFβ receptor family are also called what?

A

Receptor Serine/Threonine Protein Kinases

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2
Q

Ligands for receptor ser/thr protein kinases (TGFβ superfamily)?

A

A related superfamily of about 33 ligands in humans including the following subgroups:

  • TGFβs (transforming growth factor βs)
    • TGFβ
    • inhibins
    • activins
  • BMPs (bone morphogenetic proteins)
  • -BMPs/GDFs
    • anti-Mullerian hormone (AMH, MIS)
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3
Q

What functions do TGFβ-related ligands perform during development?

A

Regulate pattern formation, influence proliferation, differentiation, tissue remodeling, and promote cell death

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4
Q

What functions do TGFβ-related ligands perform in adults?

A

Involved in cell homeostasis, tissue repair and remodeling, inhibition of cell proliferation, and immune regulation

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5
Q

Basically, what do members of the TGFβ subgroup of receptor ser/thr protein kinase ligands do?

A

Inhibition of cell proliferation

Immune system suppression

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6
Q

Basically, what do members of the BMP subgroup of receptor ser/thr protein kinase ligands do?

A

BMP (bone morphogenetic protein) subgroup:
Osteogenesis (formation of bone)
Chondrogensis (formation of cartilage)

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7
Q

TGFβ signalling is usually ________, but can be _______, especially in cancer

A

TGFβ signalling is usually paracrine, but can be autocrine, especially in cancer

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8
Q

How is TGFβ processed?

A

TGFβ superfamily members synthesised in precursor form, contain Pro-region and Mature ligand.
Two of these precursors are dimerised, each peptide chain cleaved from their respective Pro-regions, and secreted
Once secreted, the latent form remains associated with its Pro-regions and/or other interacting biologically inactive proteins
A variety of poorly-understood mechanisms remove associated proteins which results in the biologically-active form

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9
Q

How long is mature TGFβ?

A

112 amino acids long

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10
Q

Why is signal interpretation difficult amongst the TGFβ superfamily ligands?

A

Ligands in the TGFβ superfamily can heterodimerise or homodimerise during processing, and many of these peptides have similar functions and can compensate for each other, which makes understanding their precise function difficult

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11
Q

TGFβ superfamily signalling requires what type of receptor?

A

Two types of Receptor Serine/Threonine Protein Kinases (TGFβ receptor family):
Type I: phosphorylate R-Smads
Type II: bind ligand, phosphorylate Type I receptors

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12
Q

Receptor ser/thr protein kinase Type I

A

Function: phosphorylate R-Smads
Ex: ALK1, … , ALK7

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13
Q

Receptor ser/thr protein kinase Type II

A

Function: bind ligand, phosphorylate Type I receptor on GS domain
Ex: TβRII, ActRII, ActRIIB, BMPRII, MISR

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14
Q

What is the sequence difference between receptor ser/thr kinase (TFGβ receptor family) type I and type II?

A

Approximately 40% sequence identity (both are ser/thr kinases), Type I has GS domain that is phosphorylated by Type II

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15
Q

How do TGFβ receptors bind ligand?

A

TGFβ receptors and ligands are promiscuous. Each member of the TGFβ superfamily binds to a characteristic combination of type-I and type-II receptor dimers.

  • The type II receptor dimer binds ligand first and then forms a complex with the type I receptor dimer.
  • Both receptor subunits possess serine/threonine protein kinase activity.
  • After ligand binding, the type II subunit phosphorylates a specific site (GS domain) on the type I subunit to activate its kinase activity
  • The type I receptor then phosphorylates latent transcription factors known as R-Smads (receptor Smads).
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16
Q

How many proteins make up a TGFβ receptor bound to TGFβ?

A
6
Four proteins (2 Type II and 2 Type I) come together as the heterotetrameric receptor which binds TGFβ, itself a dimer
17
Q

What genes do TGFβ target? What is the direct mediator?

A
R-Smads
↑ p21
↑ p15
↓ Myc
↓Cdc25
↓ Cyclin D
18
Q

What processes is are R-Smads directly responsible for (Smad-dependent pathways)?

A

chromatin remodelling, transcriptional regulation, miRNA processing regulation

19
Q

How are signals from TGFβ mediated?

A
  • Smad-dependent pathways (phosphorylated by type I receptor ser/thr kinases)
  • Activation of type II receptors can induce tyrosine (not ser/thr) phosphorylation of type I & II receptor, allowing them to be recognised by signalling molecules such as ShcA and Grb2, which are both adapter proteins (Grb2 leads to MAPK pathway)
20
Q

How do Smads regulate miRNAs?

A

• Smads can regulate transcription of miRNA genes:
- Directly by binding to Smad-binding elements (SBEs) which bind to cis-regulatory zones of miRNA genes
- Indirectly when the SBEs bound to Smad regulate other transcription factors that bind miRNA genes
• Smads can also regulate the processing of pri-miRNAs to pre-miRNAs by binding to the double-stranded RNA and enhancing the processing by Drosha.

21
Q

Is TGFβ a tumour suppressor or an oncogene?

A

• Normally, TGFβ is a tumour suppressing gene.
- As the cancer progresses, it becomes resistant to TGFβ tumour suppression.
• Because TGFβ affects so many functions, it can become an oncogene as cancer progresses.
-The cancer is now resistant to the tumour suppression abilities of TGFβ, but begins to use it to signal other processes that will benefit the tumour such as immune suppression, angiogenesis, and the epithelial-mesenchymal transition (cell type specification)

22
Q

How do cancerous cells become resistant to the tumour suppressor effects of TGFβ?

A

• Loss-of-functionmutationsinthecorecomponents of the pathway disable the tumor suppressor effects
– Mutated receptors: Ovarian, esophageal, head & neck, GI, colon, stomach, lung cancers
– Mutated SMAD4: Pancreas, colon, esophageal cancers
• Downstream alterations that usurp the normal functions of the pathway to cause growth promotion, i.e. this is what happens when TGFβ changes from a tumor suppressor protein to a tumor promoter protein

23
Q

ANP receptors

A

• Atrial Natriuretic Peptide (ANP) Receptors
- Receptor Guanylyl Cyclases
• ANPs are hormones secreted primarily by the heart in response to high blood pressure
• ANPs primarily act by relaxing smooth muscle cells in blood vessels and stimulating excretion of Na+ and H2O. They regulate salt and water balance and thus blood pressure
– Natriuresis is the excretion of sodium in the urine via action of the kidneys, and usually refers to the excess excretion of sodium (diuretic, anti-diuretic)
• The ANP receptors have guanylyl cyclase activity in their cytosolic domains

24
Q

How are ANPs synthesised? What are the three types?

A

ANPs are synthesized as precursor proteins that are later proteolytically processed to the final active peptide.
• ANP = atrial natriuretic peptide
• BNP = brain natriuretic
• CNP = cardiac natriuretic peptide