Cloning and characterization of mPAL, a novel Shc SH2 domain-binding protein expressed in proliferating cells

Schmandt, Rosemarie; Liu, S K; McGlade, C. Jane

doi:10.1038/sj.onc.1202507

Cited by 61 publications

(96 citation statements)

References 74 publications

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“…Shc ± SH2 has a characteristic pocket for binding phosphotyrosine, and along with residues within its bD loop showed a preference for peptides with a leucine or isoleucine at the +3 position relative to the phosphotyrosine (pY). Recently, a phosphotyrosine-independent interaction between Shc ± SH2 and mPAL, a novel protein expressed in proliferating cells, has also been identi®ed (Schmandt et al, 1999). The biological signi®cance of the Shc:mPAL interaction remains to be determined.…”

Section: Shc ± Sh2 Domainmentioning

confidence: 99%

Signaling via Shc family adapter proteins

2001

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Section: Shc ± Sh2 Domainmentioning

confidence: 99%

Signaling via Shc family adapter proteins

2001

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“…This finding established that the portion of Shc containing both the (CH1ϩSH2) domains is the minimal region required to interact with phosphorylated DDR2. To eliminate the possibility that SH2 domain is misfolded and does not associate with DDR2 in yeast, we used a truncated mouse protein expressed in activated lymphocytes (mPAL) as a positive control bait, which is known to associates with Shc SH2 (18). ␤-Galactosidase assay demonstrated that truncated mPAL associated with full-length Shc and Shc-SH2 (data not shown).…”

Section: Ddr2 Associates With Src and Its Phosphorylation Ismentioning

confidence: 99%

Discoidin Domain Receptor 2 Interacts with Src and Shc following Its Activation by Type I Collagen

Ikeda¹,

Wang²,

Torres³

et al. 2002

Journal of Biological Chemistry

124

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Discoidin domain receptor 2 (DDR2) is an unusual receptor tyrosine kinase in that its ligand is fibrillar collagen rather than a growth factor-like peptide. We examined signal transduction pathways of DDR2. Here we show that DDR2 is also unusual in that it requires Src activity to be maximally tyrosine-phosphorylated, and that Src activity also promotes association of DDR2 with Shc. The interaction with Shc involves a portion of Shc not previously implicated in interaction with receptor tyrosine kinases. These results identify Src kinase and the adaptor protein Shc as key signaling intermediates in DDR2 signal transduction. Furthermore, Src is required for DDR2-mediated transactivation of the matrix metalloproteinase-2 promoter. The data support a model in which Src and the DDR2 receptor cooperate in a regulated fashion to direct the phosphorylation of both the receptor and its targets. Receptor tyrosine kinases (RTKs)1 of the discoidin domain receptor (DDR) family are unlike most RTKs, in that they do not use typical peptide growth factors as ligands; instead, they signal in response to fibrillar collagens (1, 2), establishing the DDR family as receptors for extracellular matrix molecules. Thus far, two DDR receptors have been identified, DDR1 and DDR2. DDR1 is primarily expressed in epithelial cells in the brain, gastrointestinal tract, lung, and kidney, whereas DDR2 is expressed in interstitial cells in the heart, skeletal muscle, lung, brain, and kidney (3). DDR1 and DDR2 are differentially activated by collagens. DDR1 is activated primarily by collagen types I, II, III, V, and XI, whereas DDR2 is activated mainly by collagen types I and III (1, 2, 4).In addition to their unique ligand specification, several other features distinguish DDR receptors from other RTKs. The kinetics of DDR receptor activation by collagens differs significantly from other RTKs in response to their cognate ligands. For example, platelet-derived growth factor (PDGF) or epidermal growth factor stimulate receptor activation within seconds (4). In contrast, tyrosine phosphorylation of DDR receptors can be detected only after prolonged exposure to collagen (approximately 30 min), and then phosphorylation is sustained for an extended period (more than 16 h) (2, 5). This unique slow-on, slow-off phenomenon and receptor specificity raise important questions about the nature of downstream intracellular signals mediating the effects of DDR2.Receptor tyrosine kinases contain a catalytic domain that can autophosphorylate one or more tyrosine residues typically located in the noncatalytic region of the receptor. These phosphorylations lead to generation of docking sites for SH2 and PTB domains of signaling molecules that associate with the receptors (6). For example, PDGF receptor and fibroblast growth factor receptor associate with signaling molecules such as phospholipase C-␥, Src, Shc, and phosphatidylinositol 3-kinase. However, it is still unknown which molecules interact with DDR2.In this study, we have explored intracellular pathways medi...

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“…These interactions include: the ubiquitin-binding protein p62 and the Lck SH2 domain (15), the SHC adapter protein and the Abl SH2 domain (16), and the Cbl adapter protein and the Fyn SH2 domain (17). One report of a phosphotyrosine-independent SH2-mediated interaction involved a protein expressed in activated lymphocytes, PAL, binding to the SH2 domain of SHC (18). Since the authors were unable to detect any phosphorylation of the PAL protein, they concluded that the interaction must be phosphotyrosine-independent, if not phosphorylation-independent.…”

Section: Discussionmentioning

confidence: 99%

“…Since the authors were unable to detect any phosphorylation of the PAL protein, they concluded that the interaction must be phosphotyrosine-independent, if not phosphorylation-independent. Curiously, mutation of the conserved arginine required for phosphotyrosine-dependent binding, within the SHC SH2 domain, prevented PAL interaction (18), suggesting that more experi- ments will be required to establish the basis for this interaction.…”

Section: Discussionmentioning

confidence: 99%

“…These reports include several phosphoserine/phosphothreonine-dependent interactions (9 -14). In addition, there have been a few reports that concluded that the SH2-mediated interaction was phosphotyrosine-independent but did not determine whether or not the interaction was instead dependent upon phosphoserine or phosphothreonine (15)(16)(17)(18). In each instance, the precise amino acid residues involved in mediating these SH2 domain interactions both within the SH2 domain and on the SH2-bound ligand have yet to be identified.…”

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confidence: 99%

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Using a Phage Display Library to Identify Basic Residues in A-Raf Required to Mediate Binding to the Src Homology 2 Domains of the p85 Subunit of Phosphatidylinositol 3′-Kinase

King¹,

Fang²,

Mahon³

et al. 2000

Journal of Biological Chemistry

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Src homology 2 (SH2) domains are found in a variety of cytoplasmic proteins involved in mediating signals from cell surface receptors to various intracellular pathways. They fold as modular units and are capable of recognizing and binding to short linear peptide sequences containing a phosphorylated tyrosine residue. Here we show that each of the SH2 domains of the p85 subunit of phosphatidylinositol 3-kinase selects phage displayed peptide sequences containing the core (L/I)-A-(R/K)-I-R. The serine/threonine kinase A-Raf, containing the sequence LQRIRS, is associated with the p85 protein in both quiescent and growth factor stimulated cells. This suggests that p85 and A-Raf exist in a protein complex in cells and that complex formation does not require growth factor stimulation. We also show that p85 and A-Raf can bind directly to each other in vitro and that this interaction is mediated in part by the p85 SH2 domains. Further, the p85 SH2 domains require at least one of four distinct basic-X-basic sequence motifs within A-Raf for binding. This is the first description of a phosphotyrosine-independent SH2 domain interaction that requires basic residues on the SH2 ligand.Phosphatidylinositol 3-kinase (PI 3-kinase) 1 consists of an 85-kDa regulatory subunit (p85) and a 110-kDa catalytic subunit (p110), the latter of which is responsible for the phosphorylation of phosphatidylinositol lipids at the D3 position and serine phosphorylation of proteins (1-3). The p85 subunit contains a Src homology 3 (SH3) domain capable of binding to proline-rich sequences, a region homologous to the breakpoint cluster region (BCR) gene product, a p110 binding domain (110), and two SH2 domains. PI 3-kinase activity increases in response to platelet-derived growth factor (PDGF) binding to its receptor, in large part because the p85⅐p110 complex is relocalized from the cytosol to the lipids at the plasma membrane, by p85 SH2 domains binding directly to tyrosine phosphorylated sites on the receptor (4, 5).The SH2 domains of p85 recognize and bind to proteins such as the PDGF receptor at sites that contain a pY-X-X-M sequence (pY ϭ phosphotyrosine, X ϭ any amino acid, M ϭ methionine) in a phosphorylation-dependent manner. The residues within the p85 SH2 domain responsible for binding this sequence include a critical arginine residue that coordinates twice with the phosphate group of the phosphotyrosine residue and a hydrophobic pocket involved in methionine binding (6 -8).Over the past several years, there have also been reports of SH2 domains binding to proteins via a phosphotyrosine-independent mechanism. These reports include several phosphoserine/phosphothreonine-dependent interactions (9 -14). In addition, there have been a few reports that concluded that the SH2-mediated interaction was phosphotyrosine-independent but did not determine whether or not the interaction was instead dependent upon phosphoserine or phosphothreonine (15-18). In each instance, the precise amino acid residues involved in mediating these SH2 domain interactio...

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Cloning and characterization of mPAL, a novel Shc SH2 domain-binding protein expressed in proliferating cells

Cited by 61 publications

References 74 publications

Signaling via Shc family adapter proteins

Signaling via Shc family adapter proteins

Discoidin Domain Receptor 2 Interacts with Src and Shc following Its Activation by Type I Collagen

Using a Phage Display Library to Identify Basic Residues in A-Raf Required to Mediate Binding to the Src Homology 2 Domains of the p85 Subunit of Phosphatidylinositol 3′-Kinase

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