PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice

Jeroen Paardekooper Overman; Jae-Sung Yi; Monica Bonetti; Matthew Soulsby; Christian Preisinger; Matthew P Stokes; Li Hui; Jeffrey C Silva; John Overvoorde; Piero Giansanti; Albert J R Heck; Maria I Kontaridis; Jeroen den Hertog; Anton M Bennett

doi:10.1128/MCB.00135-14

PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice

Jeroen Paardekooper Overman, Jae-Sung Yi, Monica Bonetti, Matthew Soulsby, Christian Preisinger, Matthew P Stokes, Li Hui, Jeffrey C Silva, John Overvoorde, Piero Giansanti, Albert J R Heck, Maria I Kontaridis, Jeroen den Hertog, Anton M Bennett

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

29 Citations (Scopus)

Abstract

Noonan syndrome (NS) is an autosomal dominant disorder caused by activating mutations in the PTPN11 gene encoding Shp2, which manifests in congenital heart disease, short stature, and facial dysmorphia. The complexity of Shp2 signaling is exemplified by the observation that LEOPARD syndrome (LS) patients possess inactivating PTPN11 mutations yet exhibit similar symptoms to NS. Here, we identify "protein zero-related" (PZR), a transmembrane glycoprotein that interfaces with the extracellular matrix to promote cell migration, as a major hyper-tyrosyl-phosphorylated protein in mouse and zebrafish models of NS and LS. PZR hyper-tyrosyl phosphorylation is facilitated in a phosphatase-independent manner by enhanced Src recruitment to NS and LS Shp2. In zebrafish, PZR overexpression recapitulated NS and LS phenotypes. PZR was required for zebrafish gastrulation in a manner dependent upon PZR tyrosyl phosphorylation. Hence, we identify PZR as an NS and LS target. Enhanced PZR-mediated membrane recruitment of Shp2 serves as a common mechanism to direct overlapping pathophysiological characteristics of these PTPN11 mutations.

Original language	English
Pages (from-to)	2874-89
Number of pages	16
Journal	Molecular and Cellular Biology
Volume	34
Issue number	15
DOIs	https://doi.org/10.1128/MCB.00135-14
Publication status	Published - Aug 2014

Keywords

Animals
Female
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins
LEOPARD Syndrome
Male
Mice
Mice, Inbred C57BL
Mutation
NIH 3T3 Cells
Noonan Syndrome
Phosphorylation
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Signal Transduction
Zebrafish

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Paardekooper Overman, J., Yi, J.-S., Bonetti, M., Soulsby, M., Preisinger, C., Stokes, M. P., Hui, L., Silva, J. C., Overvoorde, J., Giansanti, P., Heck, A. J. R., Kontaridis, M. I., den Hertog, J., & Bennett, A. M. (2014). PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice. Molecular and Cellular Biology, 34(15), 2874-89. https://doi.org/10.1128/MCB.00135-14

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title = "PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice",

abstract = "Noonan syndrome (NS) is an autosomal dominant disorder caused by activating mutations in the PTPN11 gene encoding Shp2, which manifests in congenital heart disease, short stature, and facial dysmorphia. The complexity of Shp2 signaling is exemplified by the observation that LEOPARD syndrome (LS) patients possess inactivating PTPN11 mutations yet exhibit similar symptoms to NS. Here, we identify {"}protein zero-related{"} (PZR), a transmembrane glycoprotein that interfaces with the extracellular matrix to promote cell migration, as a major hyper-tyrosyl-phosphorylated protein in mouse and zebrafish models of NS and LS. PZR hyper-tyrosyl phosphorylation is facilitated in a phosphatase-independent manner by enhanced Src recruitment to NS and LS Shp2. In zebrafish, PZR overexpression recapitulated NS and LS phenotypes. PZR was required for zebrafish gastrulation in a manner dependent upon PZR tyrosyl phosphorylation. Hence, we identify PZR as an NS and LS target. Enhanced PZR-mediated membrane recruitment of Shp2 serves as a common mechanism to direct overlapping pathophysiological characteristics of these PTPN11 mutations.",

keywords = "Animals, Female, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, LEOPARD Syndrome, Male, Mice, Mice, Inbred C57BL, Mutation, NIH 3T3 Cells, Noonan Syndrome, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Signal Transduction, Zebrafish",

author = "{Paardekooper Overman}, Jeroen and Jae-Sung Yi and Monica Bonetti and Matthew Soulsby and Christian Preisinger and Stokes, {Matthew P} and Li Hui and Silva, {Jeffrey C} and John Overvoorde and Piero Giansanti and Heck, {Albert J R} and Kontaridis, {Maria I} and {den Hertog}, Jeroen and Bennett, {Anton M}",

year = "2014",

month = aug,

doi = "10.1128/MCB.00135-14",

language = "English",

volume = "34",

pages = "2874--89",

journal = "Molecular and Cellular Biology",

issn = "0270-7306",

publisher = "American Society for Microbiology",

number = "15",

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Paardekooper Overman, J, Yi, J-S, Bonetti, M, Soulsby, M, Preisinger, C, Stokes, MP, Hui, L, Silva, JC, Overvoorde, J, Giansanti, P, Heck, AJR, Kontaridis, MI, den Hertog, J & Bennett, AM 2014, 'PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice', Molecular and Cellular Biology, vol. 34, no. 15, pp. 2874-89. https://doi.org/10.1128/MCB.00135-14

TY - JOUR

T1 - PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice

AU - Paardekooper Overman, Jeroen

AU - Yi, Jae-Sung

AU - Bonetti, Monica

AU - Soulsby, Matthew

AU - Preisinger, Christian

AU - Stokes, Matthew P

AU - Hui, Li

AU - Silva, Jeffrey C

AU - Overvoorde, John

AU - Giansanti, Piero

AU - Heck, Albert J R

AU - Kontaridis, Maria I

AU - den Hertog, Jeroen

AU - Bennett, Anton M

PY - 2014/8

Y1 - 2014/8

N2 - Noonan syndrome (NS) is an autosomal dominant disorder caused by activating mutations in the PTPN11 gene encoding Shp2, which manifests in congenital heart disease, short stature, and facial dysmorphia. The complexity of Shp2 signaling is exemplified by the observation that LEOPARD syndrome (LS) patients possess inactivating PTPN11 mutations yet exhibit similar symptoms to NS. Here, we identify "protein zero-related" (PZR), a transmembrane glycoprotein that interfaces with the extracellular matrix to promote cell migration, as a major hyper-tyrosyl-phosphorylated protein in mouse and zebrafish models of NS and LS. PZR hyper-tyrosyl phosphorylation is facilitated in a phosphatase-independent manner by enhanced Src recruitment to NS and LS Shp2. In zebrafish, PZR overexpression recapitulated NS and LS phenotypes. PZR was required for zebrafish gastrulation in a manner dependent upon PZR tyrosyl phosphorylation. Hence, we identify PZR as an NS and LS target. Enhanced PZR-mediated membrane recruitment of Shp2 serves as a common mechanism to direct overlapping pathophysiological characteristics of these PTPN11 mutations.

AB - Noonan syndrome (NS) is an autosomal dominant disorder caused by activating mutations in the PTPN11 gene encoding Shp2, which manifests in congenital heart disease, short stature, and facial dysmorphia. The complexity of Shp2 signaling is exemplified by the observation that LEOPARD syndrome (LS) patients possess inactivating PTPN11 mutations yet exhibit similar symptoms to NS. Here, we identify "protein zero-related" (PZR), a transmembrane glycoprotein that interfaces with the extracellular matrix to promote cell migration, as a major hyper-tyrosyl-phosphorylated protein in mouse and zebrafish models of NS and LS. PZR hyper-tyrosyl phosphorylation is facilitated in a phosphatase-independent manner by enhanced Src recruitment to NS and LS Shp2. In zebrafish, PZR overexpression recapitulated NS and LS phenotypes. PZR was required for zebrafish gastrulation in a manner dependent upon PZR tyrosyl phosphorylation. Hence, we identify PZR as an NS and LS target. Enhanced PZR-mediated membrane recruitment of Shp2 serves as a common mechanism to direct overlapping pathophysiological characteristics of these PTPN11 mutations.

KW - Animals

KW - Female

KW - HEK293 Cells

KW - Humans

KW - Intracellular Signaling Peptides and Proteins

KW - LEOPARD Syndrome

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mutation

KW - NIH 3T3 Cells

KW - Noonan Syndrome

KW - Phosphorylation

KW - Protein Tyrosine Phosphatase, Non-Receptor Type 11

KW - Signal Transduction

KW - Zebrafish

U2 - 10.1128/MCB.00135-14

DO - 10.1128/MCB.00135-14

M3 - Article

C2 - 24865967

SN - 0270-7306

VL - 34

SP - 2874

EP - 2889

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

IS - 15

ER -

PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice

Abstract

Keywords

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