Distinct and opposite roles for SH2 and SH3 domains of v-src in embryo survival and hemangiosarcoma formation

John Christopher Morgan, John E. Majors, Deni S. Galileo

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The cellular proto-oncogene c-src is thought to be involved in formation, progression, and metastasis of a variety of tumor cell types, although its exact role during tumor cell genesis is not well defined. v-src, the viral oncogene counterpart of c-src, causes metastatic sarcomas, hemorrhagic disease, and hemangiosarcomas in chicken embryos and, thus, can be used as a constitutively activated form of src for experimentally-induced tumorigenesis. Here, we used retroviral vectors to express wild-type v-src or SH2 or SH3 domain-deleted forms (ΔSH2 or ΔSH3) to determine if different pathogenic effects resulted. Vectors were injected into early chick embryo midbrain ventricles and embryos were sacrificed at various ages up to embryonic day (E) 18. Retroviral expression of all forms of v-src resulted in transformation of pial connective tissue cells into large, rounded abnormal-appearing cells. Surprisingly, all forms of v-src were lethal. The v-src retrovirus was lethal and killed most embryos by E15 with the development of hemangiosarcomas over the injection site between E10-E12. The ΔSH3 retrovirus was the most deadly, killing most embryos by E12, however, it never resulted in hemangiosarcoma formation. The ΔSH2 retrovirus injected embryos survived longer than v-src or ΔSH3 embryos, and some of these embryos also developed large hemangiosarcomas over the injection site between E13 and E18. These results demonstrate that the src SH2 domain is required to be fully lethal, whereas the presence of the SH3 domain attenuated lethality. Furthermore, the formation of hemangiosarcomas absolutely required the presence of the src SH3 domain and to some extent required the SH2 domain. This implicates distinct and opposite roles for SH2 and SH3 domains of src and their cellular binding partners in tumorigenesis and hemorrhagic disease.

Original languageEnglish (US)
Pages (from-to)167-175
Number of pages9
JournalClinical and Experimental Metastasis
Volume22
Issue number2
DOIs
StatePublished - Jan 1 2005

Fingerprint

Hemangiosarcoma
src Homology Domains
Embryonic Structures
Retroviridae
src Genes
Carcinogenesis
Connective Tissue Cells
Injections
Chick Embryo
Mesencephalon
Sarcoma
Chickens
Neoplasms
Neoplasm Metastasis

Keywords

  • Chicken embryo
  • Hemangiosarcoma
  • Retroviral vector
  • c-src
  • v-src

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Distinct and opposite roles for SH2 and SH3 domains of v-src in embryo survival and hemangiosarcoma formation. / Morgan, John Christopher; Majors, John E.; Galileo, Deni S.

In: Clinical and Experimental Metastasis, Vol. 22, No. 2, 01.01.2005, p. 167-175.

Research output: Contribution to journalArticle

@article{b29cd565418a462aa3b78850ee54d845,
title = "Distinct and opposite roles for SH2 and SH3 domains of v-src in embryo survival and hemangiosarcoma formation",
abstract = "The cellular proto-oncogene c-src is thought to be involved in formation, progression, and metastasis of a variety of tumor cell types, although its exact role during tumor cell genesis is not well defined. v-src, the viral oncogene counterpart of c-src, causes metastatic sarcomas, hemorrhagic disease, and hemangiosarcomas in chicken embryos and, thus, can be used as a constitutively activated form of src for experimentally-induced tumorigenesis. Here, we used retroviral vectors to express wild-type v-src or SH2 or SH3 domain-deleted forms (ΔSH2 or ΔSH3) to determine if different pathogenic effects resulted. Vectors were injected into early chick embryo midbrain ventricles and embryos were sacrificed at various ages up to embryonic day (E) 18. Retroviral expression of all forms of v-src resulted in transformation of pial connective tissue cells into large, rounded abnormal-appearing cells. Surprisingly, all forms of v-src were lethal. The v-src retrovirus was lethal and killed most embryos by E15 with the development of hemangiosarcomas over the injection site between E10-E12. The ΔSH3 retrovirus was the most deadly, killing most embryos by E12, however, it never resulted in hemangiosarcoma formation. The ΔSH2 retrovirus injected embryos survived longer than v-src or ΔSH3 embryos, and some of these embryos also developed large hemangiosarcomas over the injection site between E13 and E18. These results demonstrate that the src SH2 domain is required to be fully lethal, whereas the presence of the SH3 domain attenuated lethality. Furthermore, the formation of hemangiosarcomas absolutely required the presence of the src SH3 domain and to some extent required the SH2 domain. This implicates distinct and opposite roles for SH2 and SH3 domains of src and their cellular binding partners in tumorigenesis and hemorrhagic disease.",
keywords = "Chicken embryo, Hemangiosarcoma, Retroviral vector, c-src, v-src",
author = "Morgan, {John Christopher} and Majors, {John E.} and Galileo, {Deni S.}",
year = "2005",
month = "1",
day = "1",
doi = "10.1007/s10585-005-6930-4",
language = "English (US)",
volume = "22",
pages = "167--175",
journal = "Clinical and Experimental Metastasis",
issn = "0262-0898",
publisher = "Springer Netherlands",
number = "2",

}

TY - JOUR

T1 - Distinct and opposite roles for SH2 and SH3 domains of v-src in embryo survival and hemangiosarcoma formation

AU - Morgan, John Christopher

AU - Majors, John E.

AU - Galileo, Deni S.

PY - 2005/1/1

Y1 - 2005/1/1

N2 - The cellular proto-oncogene c-src is thought to be involved in formation, progression, and metastasis of a variety of tumor cell types, although its exact role during tumor cell genesis is not well defined. v-src, the viral oncogene counterpart of c-src, causes metastatic sarcomas, hemorrhagic disease, and hemangiosarcomas in chicken embryos and, thus, can be used as a constitutively activated form of src for experimentally-induced tumorigenesis. Here, we used retroviral vectors to express wild-type v-src or SH2 or SH3 domain-deleted forms (ΔSH2 or ΔSH3) to determine if different pathogenic effects resulted. Vectors were injected into early chick embryo midbrain ventricles and embryos were sacrificed at various ages up to embryonic day (E) 18. Retroviral expression of all forms of v-src resulted in transformation of pial connective tissue cells into large, rounded abnormal-appearing cells. Surprisingly, all forms of v-src were lethal. The v-src retrovirus was lethal and killed most embryos by E15 with the development of hemangiosarcomas over the injection site between E10-E12. The ΔSH3 retrovirus was the most deadly, killing most embryos by E12, however, it never resulted in hemangiosarcoma formation. The ΔSH2 retrovirus injected embryos survived longer than v-src or ΔSH3 embryos, and some of these embryos also developed large hemangiosarcomas over the injection site between E13 and E18. These results demonstrate that the src SH2 domain is required to be fully lethal, whereas the presence of the SH3 domain attenuated lethality. Furthermore, the formation of hemangiosarcomas absolutely required the presence of the src SH3 domain and to some extent required the SH2 domain. This implicates distinct and opposite roles for SH2 and SH3 domains of src and their cellular binding partners in tumorigenesis and hemorrhagic disease.

AB - The cellular proto-oncogene c-src is thought to be involved in formation, progression, and metastasis of a variety of tumor cell types, although its exact role during tumor cell genesis is not well defined. v-src, the viral oncogene counterpart of c-src, causes metastatic sarcomas, hemorrhagic disease, and hemangiosarcomas in chicken embryos and, thus, can be used as a constitutively activated form of src for experimentally-induced tumorigenesis. Here, we used retroviral vectors to express wild-type v-src or SH2 or SH3 domain-deleted forms (ΔSH2 or ΔSH3) to determine if different pathogenic effects resulted. Vectors were injected into early chick embryo midbrain ventricles and embryos were sacrificed at various ages up to embryonic day (E) 18. Retroviral expression of all forms of v-src resulted in transformation of pial connective tissue cells into large, rounded abnormal-appearing cells. Surprisingly, all forms of v-src were lethal. The v-src retrovirus was lethal and killed most embryos by E15 with the development of hemangiosarcomas over the injection site between E10-E12. The ΔSH3 retrovirus was the most deadly, killing most embryos by E12, however, it never resulted in hemangiosarcoma formation. The ΔSH2 retrovirus injected embryos survived longer than v-src or ΔSH3 embryos, and some of these embryos also developed large hemangiosarcomas over the injection site between E13 and E18. These results demonstrate that the src SH2 domain is required to be fully lethal, whereas the presence of the SH3 domain attenuated lethality. Furthermore, the formation of hemangiosarcomas absolutely required the presence of the src SH3 domain and to some extent required the SH2 domain. This implicates distinct and opposite roles for SH2 and SH3 domains of src and their cellular binding partners in tumorigenesis and hemorrhagic disease.

KW - Chicken embryo

KW - Hemangiosarcoma

KW - Retroviral vector

KW - c-src

KW - v-src

UR - http://www.scopus.com/inward/record.url?scp=23944493687&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=23944493687&partnerID=8YFLogxK

U2 - 10.1007/s10585-005-6930-4

DO - 10.1007/s10585-005-6930-4

M3 - Article

C2 - 16086237

AN - SCOPUS:23944493687

VL - 22

SP - 167

EP - 175

JO - Clinical and Experimental Metastasis

JF - Clinical and Experimental Metastasis

SN - 0262-0898

IS - 2

ER -