Relative expression levels rather than specific activity plays the major role in determining in vivo AKT isoform substrate specificity

Rachel S Lee, Colin M House, Briony Cristiano, Ross Hannan, Richard B Pearson, Katherine Hannan

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The AKT protooncogene mediates many cellular processes involved in normal development and disease states such as cancer. The three structurally similar isoforms: AKT1, AKT2, and AKT3 exhibit both functional redundancy and isoform-specific functions; however the basis for their differential signalling remains unclear. Here we show that in vitro, purified AKT3 is approximately 47-fold more active than AKT1 at phosphorylating peptide and protein substrates. Despite these marked variations in specific activity between the individual isoforms, a comprehensive analysis of phosphorylation of validated AKT substrates indicated only subtle differences in signalling via individual isoforms in vivo. Therefore, we hypothesise, at least in this model system, that relative tissue/cellular abundance, rather than specific activity, plays the dominant role in determining AKT substrate specificity in situ.
Original languageEnglish
Pages (from-to)1 - 18
Number of pages18
JournalEnzyme Research
Volume2011
Issue number720985
DOIs
Publication statusPublished - 2011

Cite this

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title = "Relative expression levels rather than specific activity plays the major role in determining in vivo AKT isoform substrate specificity",
abstract = "The AKT protooncogene mediates many cellular processes involved in normal development and disease states such as cancer. The three structurally similar isoforms: AKT1, AKT2, and AKT3 exhibit both functional redundancy and isoform-specific functions; however the basis for their differential signalling remains unclear. Here we show that in vitro, purified AKT3 is approximately 47-fold more active than AKT1 at phosphorylating peptide and protein substrates. Despite these marked variations in specific activity between the individual isoforms, a comprehensive analysis of phosphorylation of validated AKT substrates indicated only subtle differences in signalling via individual isoforms in vivo. Therefore, we hypothesise, at least in this model system, that relative tissue/cellular abundance, rather than specific activity, plays the dominant role in determining AKT substrate specificity in situ.",
author = "Lee, {Rachel S} and House, {Colin M} and Briony Cristiano and Ross Hannan and Pearson, {Richard B} and Katherine Hannan",
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Relative expression levels rather than specific activity plays the major role in determining in vivo AKT isoform substrate specificity. / Lee, Rachel S; House, Colin M; Cristiano, Briony; Hannan, Ross; Pearson, Richard B; Hannan, Katherine.

In: Enzyme Research, Vol. 2011, No. 720985, 2011, p. 1 - 18.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Relative expression levels rather than specific activity plays the major role in determining in vivo AKT isoform substrate specificity

AU - Lee, Rachel S

AU - House, Colin M

AU - Cristiano, Briony

AU - Hannan, Ross

AU - Pearson, Richard B

AU - Hannan, Katherine

PY - 2011

Y1 - 2011

N2 - The AKT protooncogene mediates many cellular processes involved in normal development and disease states such as cancer. The three structurally similar isoforms: AKT1, AKT2, and AKT3 exhibit both functional redundancy and isoform-specific functions; however the basis for their differential signalling remains unclear. Here we show that in vitro, purified AKT3 is approximately 47-fold more active than AKT1 at phosphorylating peptide and protein substrates. Despite these marked variations in specific activity between the individual isoforms, a comprehensive analysis of phosphorylation of validated AKT substrates indicated only subtle differences in signalling via individual isoforms in vivo. Therefore, we hypothesise, at least in this model system, that relative tissue/cellular abundance, rather than specific activity, plays the dominant role in determining AKT substrate specificity in situ.

AB - The AKT protooncogene mediates many cellular processes involved in normal development and disease states such as cancer. The three structurally similar isoforms: AKT1, AKT2, and AKT3 exhibit both functional redundancy and isoform-specific functions; however the basis for their differential signalling remains unclear. Here we show that in vitro, purified AKT3 is approximately 47-fold more active than AKT1 at phosphorylating peptide and protein substrates. Despite these marked variations in specific activity between the individual isoforms, a comprehensive analysis of phosphorylation of validated AKT substrates indicated only subtle differences in signalling via individual isoforms in vivo. Therefore, we hypothesise, at least in this model system, that relative tissue/cellular abundance, rather than specific activity, plays the dominant role in determining AKT substrate specificity in situ.

UR - http://www.ncbi.nlm.nih.gov/pubmed/21869924

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DO - 10.4061/2011/720985

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EP - 18

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JF - Enzyme Research

SN - 2090-0414

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