Amino-terminal basic residues of Src mediate membrane binding through electrostatic interaction with acidic phospholipids.

Sigal, Catherine T.; Zhou, Wenjun; Buser, Carolyn A.; McLaughlin, Stuart; Resh, Marilyn D.

doi:10.1073/pnas.91.25.12253

Cited by 231 publications

(242 citation statements)

References 33 publications

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“…Cells were transfected using Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions. NIH 3T3 stable cell lines [36] expressing c-Src were maintained in DMEM/10%FBS supplemented with 0.5 g/L Geneticin (Invitrogen). Plasmid DNA amounts of 2-6 μg were used for transfections in 60 mm or 100 mm diameter dishes.…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

c-Src trafficking and co-localization with the EGF receptor promotes EGF ligand-independent EGF receptor activation and signaling

Donepudi

Resh

2008

Cellular Signalling

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Abstractc-Src is a non-receptor tyrosine kinase that associates with both the plasma membrane and endosomal compartments. In many human cancers, especially breast cancer, c-Src and the EGF Receptor (EGFR) are overexpressed. Dual overexpression of c-Src and EGFR correlates with a Src-dependent increase in activation of EGFR, and synergism between these two tyrosine kinases increases the mitogenic activity of EGFR. Despite extensive studies of the functional interaction between c-Src and EGFR, little is known about the interactions in the trafficking pathways for the two proteins and how that influences signaling. Given the synergism between c-Src and EGFR, and the finding that EGFR is internalized and can signal from endosomes, we hypothesized that c-Src and EGFR traffic together through the endocytic pathway. Here we use a regulatable c-SrcGFP fusion protein that is a bona fide marker for c-Src to show that c-Src undergoes constitutive macropinocytosis from the plasma membrane into endocytic compartments. The movement of c-Src was dependent on its tyrosine kinase activity. Stimulation of cells with EGF revealed that c-Src traffics into the cell with activated EGFR and that c-Src expression and kinase activity prolongs EGFR activation. Surprisingly, even in the absence of EGF addition, c-Src expression induced activation of EGFR and of EGFR-mediated downstream signaling targets ERK and Shc. These data suggest that the synergy between c-Src and EGFR also occurs as these two kinases traffic together, and that their colocalization promotes EGFR-mediated signaling.

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Section: Cell Culture and Transfectionmentioning

confidence: 99%

c-Src trafficking and co-localization with the EGF receptor promotes EGF ligand-independent EGF receptor activation and signaling

Donepudi

Resh

2008

Cellular Signalling

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“…Instead, other residues of Src in conjunction with myristoylation are required for mediating membrane association (Kaplan et al, 1990b). In particular, six basic residues at the amino terminus are essential for high a nity binding to lipid bilayers (Sigal et al, 1994). Moreover, three regions at the Nterminus have been identi®ed that regulate the subcellular localization of Src.…”

Section: Src Localizationmentioning

confidence: 99%

Selected glimpses into the activation and function of Src kinase

2000

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Since the discovery of the v-src and c-src genes and their products, much progress has been made in the elucidation of the structure, regulation, localization, and function of the Src protein. Src is a non-receptor protein tyrosine kinase that transduces signals that are involved in the control of a variety of cellular processes such as proliferation, di erentiation, motility, and adhesion. Src is normally maintained in an inactive state, but can be activated transiently during cellular events such as mitosis, or constitutively by abnormal events such as mutation (i.e. v-Src and some human cancers). Activation of Src occurs as a result of disruption of the negative regulatory processes that normally suppress Src activity, and understanding the various mechanisms behind Src activation has been a target of intense study. Src associates with cellular membranes, in particular the plasma membrane, and endosomal membranes. Studies indicate that the di erent subcellular localizations of Src could be important for the regulation of speci®c cellular processes such as mitogenesis, cytoskeletal organization, and/or membrane tra cking. This review will discuss the history behind the discovery and initial characterization of Src and the regulatory mechanisms of Src activation, in particular, regulation by modi®cation of the carboxyterminal regulatory tyrosine by phosphatases and kinases. Its focus will then turn to the di erent subcellular localizations of Src and the possible roles of nuclear and perinuclear targets of Src. Finally, a brief section will review some of our present knowledge regarding Src involvement in human cancers. Oncogene (2000) 19, 5620 ± 5635.

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“…Integral membrane proteins like CD36, SNAP-25 and caveolin-1 contain several palmitoylation Rodgers et al, 1994;Sigal et al, 1994;Webb et al, 2000) sites adjacent to, or just within, the cytoplasmic leaflet of the membrane (Jochen & Hays, 1993;Monier et al, 1996;Veit et al, 1996a, b). Insertion of the palmitoyl chain into the lipid bilayer is energetically favourable and may provide the driving force for partitioning the modified protein into the raft environment (Schroeder et al, 1994).…”

Section: The Raft Passengersmentioning

confidence: 99%

“…Therefore, myristoylated proteins can only maintain an efficient membrane interaction when a second membrane-binding site is present. This second membranebinding site can be created by a nearby stretch of basic residues or palmitoyl chains, as in the Src family of protein kinases or the a subunits of heterotrimeric G proteins Robbins et al, 1995;Rodgers et al, 1994;Sigal et al, 1994).…”

Section: The Raft Passengersmentioning

confidence: 99%

Do lipid rafts mediate virus assembly and pseudotyping?

Briggs

Wilk

Fuller

2003

Journal of General Virology

114

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Amino-terminal basic residues of Src mediate membrane binding through electrostatic interaction with acidic phospholipids.

Abstract: Membrane targeting of pp6w0 (Src) is mediated by its myristoylated amino terminus. We demonstrate that, in addition to myristate, six basic residues in the amino terminus are essential for high-affinity binding to the lipid bilayer via electrostatic interaction with acidic phospholipids.

Cited by 231 publications

References 33 publications

c-Src trafficking and co-localization with the EGF receptor promotes EGF ligand-independent EGF receptor activation and signaling

c-Src trafficking and co-localization with the EGF receptor promotes EGF ligand-independent EGF receptor activation and signaling

Selected glimpses into the activation and function of Src kinase

Do lipid rafts mediate virus assembly and pseudotyping?

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