Cbl functions downstream of Src kinases in FCγRI signaling in primary human macrophages

  title={Cbl functions downstream of Src kinases in FC$\gamma$RI signaling in primary human macrophages},
  author={Anat Erdreich-Epstein and M. Liu and Anita M. Kant and Kayvon D. Izadi and Jan A. Nolta and Donald L Durden},
  journal={Journal of Leukocyte Biology},
Cbl is a cytosolic protein that is rapidly tyrosine phosphorylated in response to Fc receptor activation and binds to the adaptor proteins Grb2, CrkL, and Nck. A few reports describe Cbl interactions in primary human hematopoietic cells. We show evidence that Cbl participates in signaling initiated by FcγRI receptor cross‐linking in human primary macrophages, and functions downstream of Src family kinases in this pathway. FcγRI stimulation in human macrophages was associated with rapid and… 

A PKC-SHP1 signaling axis desensitizes Fcγ receptor signaling by reducing the tyrosine phosphorylation of CBL and regulates FcγR mediated phagocytosis

The results suggest a functional model by which PKC interacts with SHP1 to affect the phosphorylation state of CBL, the activation state of Rac and the negative regulation of ITAM signaling i.e. Fcγ receptor mediated phagocytosis.

Phagocytosis in Macrophages Lacking Cbl Reveals an Unsuspected Role for Fcγ Receptor Signaling and Actin Assembly in Target Binding1

Findings suggest that dynamic engagement of TKs and the cytoskeleton enables macrophages to serve as cellular “Venus fly traps”, with the capacity to capture phagocytic targets under conditions of limiting opsonin density.

Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell–mediated immune responses

HPK1 deficiency resulted in enhanced TCR-induced phosphorylation of SLP-76, phospholipase C-γ1 and the kinase Erk, more-persistent calcium flux, and increased production of cytokines and antigen-specific antibodies.

Repression of c-Cbl leads to enhanced G-CSF Jak-STAT signaling without increased cell proliferation

The data suggest that physiologic level of c-Cbl provides a growth stimulatory pathway for G-CSF and that enhanced Jak-STAT activation is not sufficient for G -CSF-induced growth.

Cbl–phosphatidylinositol 3 kinase interaction differentially regulates macrophage colony‐stimulating factor‐mediated osteoclast survival and cytoskeletal reorganization

Results indicate that abrogation of the Cbl–PI3K interaction, although not affecting M‐CSF‐induced proliferation and differentiation of precursors, is required for regulation of survival and actin cytoskeletal reorganization of mature osteoclasts.

Enhanced Phagocytosis in Neonatal Monocyte-Derived Macrophages is Associated with Impaired SHP-1 Signaling

The data suggest that the enhanced phagocytic capacity of neonatal MDM was enhanced in comparison to adult MDM is associated with decreased SHP-1 activity and alteration of downstream signaling pathways.

The Cbl family proteins: Ring leaders in regulation of cell signaling

This review will endeavor to provide a summary of current studies focused on the effects of Cbl proteins on various biological processes and the mechanism of these effects.

The diverse functions of Src family kinases in macrophages.

  • C. AbramC. Lowell
  • Biology
    Frontiers in bioscience : a journal and virtual library
  • 2008
The cytoplasmic tyrosine kinase Src and its family members (SFKs) have been implicated in many intracellular signaling pathways in macrophages, but it has been difficult to implicate any given member of the family in any specific pathway.

Expression and tyrosine phosphorylation of Cbl regulates macrophage chemokinetic and chemotactic movement

Results suggest that Cbl is likely to be an important downstream mediator of the Src family kinase‐regulated macrophage motility pathway.

Macrophage Stimulating Protein (MSP) evokes superoxide anion production by human macrophages of different origin

It is shown that human recombinant MSP evokes a dose‐dependent superoxide anion production in human alveolar and peritoneal macrophage as well as in monocyte‐derived macrophages, but not in circulating human monocytes, suggesting for the MSP/Ron complex a role of activator as well of possible marker for human mature macrophaging.



CBL-GRB2 interaction in myeloid immunoreceptor tyrosine activation motif signaling.

The data demonstrate that the CBL-GRB2 and GRB2-SOS protein complexes are distinct and mutually exclusive in U937IF cells, supporting a model by which the C BL-GRb2 and GrB2 -SOS complexes function in separate pathways for myeloid Fc gammaRI signaling.

Interactions of Cbl with Two Adaptor Proteins, Grb2 and Crk, upon T Cell Activation (*)

The results suggest that different adaptor proteins may have different roles in the regulation of c-cbl proto-oncogene product, andTyrosine-phosphorylated Cbl binds exclusively to the SH2 domain of Crk, another SH2/SH3 domain-containing protein, upon TCR stimulation.

Interactions of Cbl with Grb2 and phosphatidylinositol 3'-kinase in activated Jurkat cells

Cbl function in Jurkat T cells involves its constitutive association with Grb2 and its recruitment of PI 3-kinase in response to TCR activation, suggesting that Sos-GrB2 and Cbl-Grb2 are present as distinct complexes.

Tyrosine Phosphorylation and Translocation of the c-Cbl Protein after Activation of Tyrosine Kinase Signaling Pathways (*)

The c-cbl protooncogene product (c-Cbl) is a 120-kDa protein that has been shown to bind to the Src homology 3 domains of various proteins, suggesting its involvement in signal transduction pathways.

Stimulation through the T Cell Receptor Induces Cbl Association with Crk Proteins and the Guanine Nucleotide Exchange Protein C3G (*)

Cbl associates with all three forms of the human Crk protein, predominantly CrkL, following T cell receptor activation of Jurkat T cells, suggesting the possibility that Cbl may participate in a signaling pathway that regulates guanine nucleotide exchange on small G-proteins in T cells.

Formation of Shc/Grb2- and Crk adaptor complexes containing tyrosine phosphorylated Cbl upon stimulation of the B-cell antigen receptor.

The BCR activates Shc/Grb2-, Grb2- and Crk adaptor complexes of distinct composition, which may allow selective coupling to different signal transduction cascades and point to a central role for this molecule in the regulation of antigen receptor-induced B cell responses.

Erythropoietin and interleukin-3 activate tyrosine phosphorylation of CBL and association with CRK adaptor proteins.

The data suggest that the inducible Cbl-Crk association is a proximal component of a signaling pathway downstream of multiple cytokine receptors, and particularly important in factor-dependent hematopoietic cell lines.

The SH2 and SH3 domain-containing Nck protein is oncogenic and a common target for phosphorylation by different surface receptors

It is shown that epidermal growth factor or platelet-derived growth factor stimulation of intact human or murine cells leads to phosphorylation of Nck protein on tyrosine, serine, and threonine residues, which shows that Nck is an oncogenic protein and a common target for the action of different surface receptors.

Specific Association of Tyrosine-phosphorylated c-Cbl with Fyn Tyrosine Kinase in T Cells*

It is demonstrated here that the association of Fyn and c-Cbl is direct and does not require the presence of other proteins, and it is demonstrated that Fyn is the Src family kinase that preferentially interacts with c- Cbl in T cells.