Cloning and characterization of a novel adaptor protein, CIN85, that interacts with c-Cbl

H Take1, S Watanabe, K Takeda

  • 1Hematology Branch, National Institutes of Health, Bethesda, Maryland, 20892, USA.

Insights

Researchers discovered CIN85, a novel protein that interacts with c-Cbl. This interaction is crucial for epidermal growth factor (EGF) receptor signaling pathways.

Area of Science:

  • Molecular and Cellular Biology
  • Signal Transduction
  • Oncogene Research

Background:

  • The c-Cbl proto-oncogene product is a key substrate for protein tyrosine kinases.
  • c-Cbl undergoes rapid tyrosine phosphorylation upon stimulation of various cell-surface receptors, indicating its role in signaling pathways.

Purpose of the Study:

  • To identify novel proteins interacting with c-Cbl.
  • To investigate the role of a newly identified c-Cbl-interacting protein, CIN85, in cellular signaling.

Main Methods:

  • Identification and characterization of CIN85, an 85 kDa protein.
  • Analysis of CIN85 mRNA expression in human tissues and cancer cell lines.
  • Investigation of CIN85-c-Cbl interaction using biochemical assays, focusing on the role of CIN85's SH3 domains.
  • Stimulation of 293 cells with epidermal growth factor (EGF) to study dynamic changes in CIN85-c-Cbl association and c-Cbl phosphorylation.

Main Results:

  • A novel c-Cbl-interacting protein, CIN85, was identified, sharing similarities with adaptor proteins CMS and CD2AP.
  • CIN85 mRNA is ubiquitously expressed in normal human tissues and cancer cell lines.
  • CIN85 was found to be constitutively associated with c-Cbl, with the second SH3 domain of CIN85 being critical for this interaction.
  • The association between CIN85 and c-Cbl was transiently enhanced upon EGF stimulation, correlating with c-Cbl tyrosine phosphorylation levels.

Conclusions:

  • CIN85 is a novel adaptor protein that interacts with c-Cbl.
  • The interaction between CIN85 and c-Cbl is regulated by EGF stimulation and c-Cbl phosphorylation.
  • CIN85 likely plays a specific role in the epidermal growth factor receptor (EGFR) signaling cascade through its interaction with c-Cbl.

Related Concept Videos

Catenins01:23

Catenins

Catenins are characterized by multiple binding domains and dynamic structures that allow them to function as linker proteins in cell junction complexes. All catenins, except α-catenin, contain a characteristic protein sequence called the armadillo repeat and are therefore also called armadillo proteins.
Catenins in Cell Junctions
Catenins bind to cell adhesion molecules such as cadherins and link them to different cytoskeletal proteins depending on the type of cell junction. At the adherens...
Anaphase Promoting Complex00:50

Anaphase Promoting Complex

The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Clathrin Coated Vesicles01:12

Clathrin Coated Vesicles

Clathrin-coated vesicles use endocytosis to transport receptors and lysosomal hydrolases from the Golgi to the lysosome in the late secretory pathway. Clathrin-mediated endocytosis was the first described endocytic process, and Clathrin-coated vesicles remain one of the most well-studied transport vesicles. The molecular machinery that generates clathrin-coated vesicles comprises over 50 proteins that precisely coordinate vesicle formation. Cell surface receptors concentrated in indented sites...
Adaptability of Cytoskeletal Filaments01:12

Adaptability of Cytoskeletal Filaments

The cytoskeleton is a complex dynamic structure performing varied functions based on cellular requirements. The adaptability of the individual filaments in the cytoskeleton determines their ability to perform various functions within the cell. It can undergo rapid reorganization during processes like cell division or remain stable for several hours as in the interphase. The adaptability of these filaments depends on stringent regulatory mechanisms. The microfilament and microtubules of the...
Protein Complexes with Interchangeable Parts01:57

Protein Complexes with Interchangeable Parts

Groups of proteins may form a complex where each protein in this complex has a different role in the overall execution of the complex’s function. Often some of the proteins in the complex can be replaced by a closely related variant to give a complex that contains many of the same components yet is functionally distinct.
The SCF ubiquitin ligase is a protein complex of five individual proteins. This complex attaches ubiquitin to other target proteins to mark them for degradation. In order to...