Research ArticleImmunology

The adaptor protein CIN85 assembles intracellular signaling clusters for B cell activation

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Science Signaling  28 Jun 2016:
Vol. 9, Issue 434, pp. ra66
DOI: 10.1126/scisignal.aad6275

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Controlling signaling through clustering

Several cell surface receptors require the multidomain protein CIN85 for signaling. Kühn et al. elucidated its mode of action in B lymphocytes in which CIN85 associates with the adaptor protein SLP-65, which transmits activation signals from the B cell receptor (BCR). NMR spectroscopy and X-ray crystallography showed that CIN85 formed a stable trimer through its C-terminal, coiled-coil domain. The SH3 domains of CIN85 recruited multiple SLP-65 molecules that in turn bound to other CIN85 trimers, resulting in the formation of large CIN85–SLP-65 signaling clusters. Manipulating the oligomerization state of SLP-65 affected the efficiency of BCR signaling, which suggests that CIN85 sets the threshold for B cell activation by controlling the size of SLP-65 signaling clusters.


The adaptor molecule Cbl-interacting protein of 85 kD (CIN85) regulates signaling from a number of cell surface receptors, such as growth factor receptors and antigen receptors on lymphocytes. Because of its multidomain structure, CIN85 is thought to act as a classical adaptor protein that connects functionally distinct components of a given signaling pathway through diverse protein domains. However, we found that in B lymphocytes, CIN85 functions to oligomerize SLP-65, which is the central effector protein of the B cell receptor (BCR). Therefore, CIN85 trimerizes through a carboxyl-terminal, coiled-coil domain. The multiple Src homology 3 (SH3) domains of trimeric CIN85 molecules associated with multiple SLP-65 molecules, which recruited further CIN85 trimers, thereby perpetuating the oligomerization process. Formation of this oligomeric signaling complex in resting B cells rendered the cells poised for the efficient initiation of intracellular signaling upon BCR stimulation. Our data suggest that the functionality of signaling cascades does not rely solely on the qualitative linkage of their various components but requires a critical number of effectors to become concentrated in signaling complexes.

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