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Mechanism of inhibition of TGF β receptor by FKBP12…

Mechanism of inhibition of TGF β receptor by FKBP12…. Basma Sarfraz 17.04.2013. TGF β Super family….

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Mechanism of inhibition of TGF β receptor by FKBP12…

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  1. Mechanism of inhibition of TGFβ receptor by FKBP12… Basma Sarfraz 17.04.2013

  2. TGFβ Super family… • Transforming growth factor beta (TGF-β) controls proliferation, cellular differentiation- to inhibit cell cycle progression and promote apoptosis that together significantly contribute to the tumor suppressive role for TGF-beta during carcinoma initiation and progression. • Secreted by many cell types, including macrophages and other functions in most cells that exists in at least threeisoforms called TGF-β1, TGF-β2 and TGF-β3.  • Most tissues have high expression of the gene encoding TGF-β.

  3. TGFβ signaling… • Ligand-TGFβ • Receptors – TβR-ll and TβR-l FKBP12 L l ll P R-SMAD’s P

  4. Inhibition of TβR-1 by FKBP12… Activating phosphorylation site Rapamycin b.pocket Rapamycin Purpose: Investigate the mechanism and functional significance of this effect. FKBP12 Leu-Pro b.pocket TβR-1 Leu-Pro sequence Mutation: Abolish interaction between these proteins.

  5. Role of every molecular component invole in this mechanism… TGFβ receptors • TβR-l and TβR-llcomprises intrinsic affinity for each other. • Leads to their ligand independent activation. • Evidences: • Our results show that TβR-I mutants defective in FKBP12 binding (‘FKBP12-blind’ mutants) have an elevated signaling activity compared with wild-type TβR-I. • The signaling advantage of these mutants is also observed at low concentrations of added TGF and progressively disappears at higher concentrations. • Overexpression of FKBP12 inhibits signaling by TβR-I.

  6. FKBP12… • Ubiquitous and relatively abundant. • Exhibit high specificity in binding to immunosuppressive agent. • Interact with many members of the TGFβ type I receptor family- inhibit association of TGFβ receptors. • Binds to Leu-Pro sequence of TβR-l –blocks association with TβR-ll . • Provide safeguard against leaky TGFβsignaling. • Mutation in any of them ( TβR-l and FKBP12 ) abolish interaction between these two- loses function.

  7. One of the role of FKBP12…

  8. Rapamycin.. • Blocks FKβP12 by binding to its Rapamycin binding pocket. • Inhibits its interaction with TβR-l –allow TGFβ receptors to undergo ligand independent activation.

  9. THANKYOU…

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