Protein phosphatases

Protein phosphatase acting

as a reset button for kinases

this action is eithera) inactivating

orb) activating

like for protein kinases, a distinction is made between tyrosine and threonine/serine phosphatases

As there is always an exception to the rule: certain phosphatases recognize both phosphotyrosine and

phosphothreonine/serine residues

these are the dual specificity phosphatases

serinethreonine

tyrosine

serinethreoninetyrosine

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The depth of the catalytic pocket is one of the determinants of phosphoresidue specificity of the protein phosphatase

Serine / threonine phosphatases

Mechanism of action and highly conserved (signature) sequences of serine / threonine protein phosphatases. The catalytic subunits have broad specificity

Specificity of serine/threonine phosphatases is largely determined by association of regulatory subunits that affect subcellular localisation as well

as substrate specificity

The regulatory subunit MYPT1 turns the broad-specificity PP1C (catalytic subunit) into a myosin regulatory-light chain-specific phosphatase

- R= arginine & K= lysine are positively charged residues that fit the negatively charged acidic groove- Dephosphorylation of myosin regulatory light chain causes smooth muscle cell relaxation (no hydrolysis of ATP)

Role of the phosphatase calcineurin in antigen-mediated T-cell activation (followed by clonal expansion (adaptive immunity))

the activated T-cell receptor induces a Ca2+ signal that binds calcineurin and activates the catalytic subunit (CnA) (PP2B), leading to dephosphorylation

and nuclear translocation of the transcription factor NFAT

NFAT=nuclear factor of activated T-cells

action of protein phosphatase

tyrosine protein phosphates (PTP)

two step mechanism of action of protein tyrosine phosphatases

Tyrosine phosphatase as an inactivator of insulin signalling: tyrosine phosphatase 1B (PTP1B) dephosphorylates the insulin receptor

Certain tyrosine phosphatases have tumour suppressor

functions (by opposing to deragulated tyrosine

protein kinases)

tyrosine phosphatase as an activator of Src: dephosphorylation of the

C-terminal tyrosine phosphate by CD45

the SH2 domain bound to the C-

terminal phosphotyrosine

keeps the kinase in an incompetent conformation

dephosphorylation removes this

constraint and is followed by

autophosphorylation. The kinase is now

fully competent

PTEN qualifies by its structure and its sequence as a tyrosine phosphatase but it prefers inositol lipids

and acts as a inositol lipid phosphatase (important tumour suppressor role)

PTEN removes the phosphates that have been added by PI 3-kinase

PI 3-kinase is activated by growth factors (including insulin) and plays an important role in growth regulation and cell survival

this explains why loss of PTEN is involved in cell transformation(cancer development)