SH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding

Brian, Ben F; Sjaastad, Frances V.; Freedman, Tanya S.

doi:10.1038/s41598-022-09589-9

Cited by 6 publications

(7 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, PEAK2 was identified as a new CSK substrate uncovering a feed-forward CSK activation loop that promotes cell motility [ 19 ]. Consistent with this, we observed that PEAK2 promoted CSK tyrosine phosphorylation on Tyr18 lying in its SH3 domain, which may affect CSK-SH3 binding capacity, enabling kinase dimerization and phosphosignalling [ 48 , 49 ]. While CSK displays antioncogenic activity in some cancers by inactivation of SFKs, this mechanism is impaired in CRC [ 37 , 50 ].…”

Section: Discussionsupporting

confidence: 55%

Oncogenic Signalling of PEAK2 Pseudokinase in Colon Cancer

Lecointre

Fourgous

Montarras

et al. 2022

Cancers

View full text Add to dashboard Cite

The PEAK family pseudokinases are essential components of tyrosine kinase (TK) pathways that regulate cell growth and adhesion; however, their role in human cancer remains unclear. Here, we report an oncogenic activity of the pseudokinase PEAK2 in colorectal cancer (CRC). Notably, high PRAG1 expression, which encodes PEAK2, was associated with a bad prognosis in CRC patients. Functionally, PEAK2 depletion reduced CRC cell growth and invasion in vitro, while its overexpression increased these transforming effects. PEAK2 depletion also reduced CRC development in nude mice. Mechanistically, PEAK2 expression induced cellular protein tyrosine phosphorylation, despite its catalytic inactivity. Phosphoproteomic analysis identified regulators of cell adhesion and F-actin dynamics as PEAK2 targets. Additionally, PEAK2 was identified as a novel ABL TK activator. In line with this, PEAK2 expression localized at focal adhesions of CRC cells and induced ABL-dependent formation of actin-rich plasma membrane protrusions filopodia that function to drive cell invasion. Interestingly, all these PEAK2 transforming activities were regulated by its main phosphorylation site, Tyr413, which implicates the SRC oncogene. Thus, our results uncover a protumoural function of PEAK2 in CRC and suggest that its deregulation affects adhesive properties of CRC cells to enable cancer progression.

show abstract

Section: Discussionsupporting

confidence: 55%

Oncogenic Signalling of PEAK2 Pseudokinase in Colon Cancer

Lecointre

Fourgous

Montarras

et al. 2022

Cancers

View full text Add to dashboard Cite

show abstract

“…PTPN22 is an important inhibitor of the TCR signal pathway [16]. It dephosphorylates protein tyrosine kinases or interacts with C‐terminal c‐Src kinase (Csk) to inhibit T cell activation [42–44]. According to our previous study, PTPN22 dephosphorylates essectial proteins in the TCR signal pathway by binding to EB1 and inhibits TCR‐mediated T cell activation, whereas EB1 competes with Csk in binding to PTPN22 [20].…”

Section: Discussionmentioning

confidence: 99%

PTPN22 activates the PI3K pathway via 14‐3‐3τ in T cells

et al. 2023

View full text Add to dashboard Cite

The protein tyrosine phosphatase PTPN22 inhibits T cell activation by dephosphorylating some essential proteins in the T cell receptor‐mediated signalling pathway, and its negative regulatory function protects organisms from autoimmune disease. 14‐3‐3τ is an adaptor protein that regulates target protein function through its intracellular localization. In the present study, we determined that PTPN22 binds to 14‐3‐3τ via the PTPN22‐Ser640 phosphorylation side. PTPN22 binding to 14‐3‐3τ resulted in 14‐3‐3τ‐Tyr179 dephosphorylation, and reduced the association between 14‐3‐3τ and Shc, which competitively increased 14‐3‐3ζ binding to Shc and activated phosphoinositide 3‐kinase (PI3K) by bringing it to the membrane. In addition, PTPN22 decreased the tyrosine phosphorylation of p110 to activate PI3K. These two pathways cooperatively affect PI3K activity and the expression of PI3K downstream proteins, such as phosphorylated Akt, mammalian target of rapamycin and forkhead box O1, which inhibited the expression of some proinflammatory factors such as interleukin‐1β, interleukin‐2, interleukin‐6, interferon‐γ and tumour necrosis factor‐α. Our research provides a preliminary theory for PTPN22 regulating T cell activation, development and immune response via the PI3K/Akt/mammalian target of rapamycin pathway and brings new information for clarifying the functions of PTPN22 in autoimmune diseases.

show abstract

“…Because SFK inactivation requires the dephosphorylation of the activation loop Tyr and the phosphorylation of the C-terminal tail Tyr, the Csk-phosphatase complex can more effectively inactivate SFKs. Interestingly, Csk can also homodimerize through its SH3 domain in vitro (Levinson et al, 2009) and in Jurkat T-cell (Brian et al, 2022), and the dimerization precludes the binding of the Csk to the phosphatases. Mutations in the Csk SH3 domain can selectively disrupt the dimerization or phosphatase binding, indicating overlapping but not identical interfaces for the two types of interactions (Brian et al, 2022).…”

Section: Csk Regulation By Domain-domain Interactionmentioning

confidence: 99%

“…Interestingly, Csk can also homodimerize through its SH3 domain in vitro (Levinson et al, 2009) and in Jurkat T-cell (Brian et al, 2022), and the dimerization precludes the binding of the Csk to the phosphatases. Mutations in the Csk SH3 domain can selectively disrupt the dimerization or phosphatase binding, indicating overlapping but not identical interfaces for the two types of interactions (Brian et al, 2022). These studies suggest a more complex regulation of Csk function by protein-protein interactions that can manipulate the basic catalytic function of Csk.…”

Section: Csk Regulation By Domain-domain Interactionmentioning

confidence: 99%

Dissection of the catalytic and regulatory structure-function relationships of Csk protein tyrosine kinase

Sun

Ayrapetov

2023

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Protein tyrosine kinases (PTKs) are a large enzyme family that regulates many cellular processes. The key to their broad role in signaling is their tunable substrate specificity and regulatory mechanisms that allow each to respond to appropriate regulatory signals and phosphorylate the correct physiological protein substrates. Thus, in addition to the general PTK catalytic platform, each PTK acquires unique structural motifs that confer a unique combination of catalytic and regulatory properties. Understanding the structural basis for these properties is essential for understanding and manipulating the PTK-based signaling networks in normal and cancer cells. C-terminal Src kinase (Csk) and its homolog, Csk-homologous kinase (Chk), phosphorylate Src family kinases on a C-terminal Tyr residue and negatively regulate their kinase activity. While this regulatory function is biologically essential, Csk and Chk have also been excellent model PTKs for dissecting the structural basis of PTK catalysis and regulation. In this article, we review the structure-function studies of Csk and Chk that shed light on the regulatory and catalytic mechanisms of protein tyrosine kinases in general.

show abstract

SH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding

Cited by 6 publications

References 69 publications

Oncogenic Signalling of PEAK2 Pseudokinase in Colon Cancer

Oncogenic Signalling of PEAK2 Pseudokinase in Colon Cancer

PTPN22 activates the PI3K pathway via 14‐3‐3τ in T cells

Dissection of the catalytic and regulatory structure-function relationships of Csk protein tyrosine kinase

Contact Info

Product

Resources

About