A Cancer-Associated Mutation in Atypical Protein Kinase C iota Occurs in a Substrate-Specific Recruitment Motif

Mark Linch; Marta Sanz-Garcia; Erika Soriano; Yixiao Zhang; Philippe Riou; Carine Rosse; Angus Cameron; Phillip Knowles; Andrew Purkiss; Svend Kjaer; Neil Q. McDonald; Peter J. Parker

doi:10.1126/scisignal.2004068

A Cancer-Associated Mutation in Atypical Protein Kinase C iota Occurs in a Substrate-Specific Recruitment Motif

Mark Linch, Marta Sanz-Garcia, Erika Soriano, Yixiao Zhang, Philippe Riou, Carine Rosse, Angus Cameron, Phillip Knowles, Andrew Purkiss, Svend Kjaer, Neil Q. McDonald^*, Peter J. Parker

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

25 Citations (Scopus)

Abstract

Atypical protein kinase C tau (PKC tau) has roles in cell growth, cellular polarity, and migration, and its abundance is frequently increased in cancer. We identified a protein interaction surface containing a dibasic motif (RIPR) that bound a distinct subset of PKC tau substrates including lethal giant larvae 2 (LLGL2) and myosin X, but not other substrates such as Par3. Further characterization demonstrated that Arg(471) in this motif was important for binding to LLGL2, whereas Arg(474) was critical for interaction with myosin X, indicating that multiple complexes could be formed through this motif. A somatic mutation of the dibasic motif (R471C) was the most frequent mutation of PKC iota in human cancer, and the intact dibasic motif was required for normal polarized epithelial morphogenesis in three-dimensional cysts. Thus, the R471C substitution is a change-of-function mutation acting at this substrate-specific recruitment site to selectively disrupt the polarizing activity of PKC iota.

Original language	English
Article number	ra82
Number of pages	11
Journal	Science Signaling
Volume	6
Issue number	293
DOIs	https://doi.org/10.1126/scisignal.2004068
Publication status	Published - 17 Sept 2013

Keywords

MYOSIN-X
POLARITY PROTEIN
EPITHELIAL-CELLS
PKC-IOTA
UNCONVENTIONAL MYOSIN
TRANSFORMED GROWTH
CATALYTIC DOMAIN
TIGHT JUNCTION
POOR-PROGNOSIS
EGF RECEPTOR

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "A Cancer-Associated Mutation in Atypical Protein Kinase C iota Occurs in a Substrate-Specific Recruitment Motif",

abstract = "Atypical protein kinase C tau (PKC tau) has roles in cell growth, cellular polarity, and migration, and its abundance is frequently increased in cancer. We identified a protein interaction surface containing a dibasic motif (RIPR) that bound a distinct subset of PKC tau substrates including lethal giant larvae 2 (LLGL2) and myosin X, but not other substrates such as Par3. Further characterization demonstrated that Arg(471) in this motif was important for binding to LLGL2, whereas Arg(474) was critical for interaction with myosin X, indicating that multiple complexes could be formed through this motif. A somatic mutation of the dibasic motif (R471C) was the most frequent mutation of PKC iota in human cancer, and the intact dibasic motif was required for normal polarized epithelial morphogenesis in three-dimensional cysts. Thus, the R471C substitution is a change-of-function mutation acting at this substrate-specific recruitment site to selectively disrupt the polarizing activity of PKC iota.",

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author = "Mark Linch and Marta Sanz-Garcia and Erika Soriano and Yixiao Zhang and Philippe Riou and Carine Rosse and Angus Cameron and Phillip Knowles and Andrew Purkiss and Svend Kjaer and McDonald, {Neil Q.} and Parker, {Peter J.}",

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AU - Linch, Mark

AU - Sanz-Garcia, Marta

AU - Soriano, Erika

AU - Zhang, Yixiao

AU - Riou, Philippe

AU - Rosse, Carine

AU - Cameron, Angus

AU - Knowles, Phillip

AU - Purkiss, Andrew

AU - Kjaer, Svend

AU - McDonald, Neil Q.

AU - Parker, Peter J.

PY - 2013/9/17

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N2 - Atypical protein kinase C tau (PKC tau) has roles in cell growth, cellular polarity, and migration, and its abundance is frequently increased in cancer. We identified a protein interaction surface containing a dibasic motif (RIPR) that bound a distinct subset of PKC tau substrates including lethal giant larvae 2 (LLGL2) and myosin X, but not other substrates such as Par3. Further characterization demonstrated that Arg(471) in this motif was important for binding to LLGL2, whereas Arg(474) was critical for interaction with myosin X, indicating that multiple complexes could be formed through this motif. A somatic mutation of the dibasic motif (R471C) was the most frequent mutation of PKC iota in human cancer, and the intact dibasic motif was required for normal polarized epithelial morphogenesis in three-dimensional cysts. Thus, the R471C substitution is a change-of-function mutation acting at this substrate-specific recruitment site to selectively disrupt the polarizing activity of PKC iota.

AB - Atypical protein kinase C tau (PKC tau) has roles in cell growth, cellular polarity, and migration, and its abundance is frequently increased in cancer. We identified a protein interaction surface containing a dibasic motif (RIPR) that bound a distinct subset of PKC tau substrates including lethal giant larvae 2 (LLGL2) and myosin X, but not other substrates such as Par3. Further characterization demonstrated that Arg(471) in this motif was important for binding to LLGL2, whereas Arg(474) was critical for interaction with myosin X, indicating that multiple complexes could be formed through this motif. A somatic mutation of the dibasic motif (R471C) was the most frequent mutation of PKC iota in human cancer, and the intact dibasic motif was required for normal polarized epithelial morphogenesis in three-dimensional cysts. Thus, the R471C substitution is a change-of-function mutation acting at this substrate-specific recruitment site to selectively disrupt the polarizing activity of PKC iota.

KW - MYOSIN-X

KW - POLARITY PROTEIN

KW - EPITHELIAL-CELLS

KW - PKC-IOTA

KW - UNCONVENTIONAL MYOSIN

KW - TRANSFORMED GROWTH

KW - CATALYTIC DOMAIN

KW - TIGHT JUNCTION

KW - POOR-PROGNOSIS

KW - EGF RECEPTOR

U2 - 10.1126/scisignal.2004068

DO - 10.1126/scisignal.2004068

M3 - Article

SN - 1945-0877

VL - 6

JO - Science Signaling

JF - Science Signaling

IS - 293

M1 - ra82

ER -

A Cancer-Associated Mutation in Atypical Protein Kinase C iota Occurs in a Substrate-Specific Recruitment Motif

Abstract

Keywords

UN SDGs

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