PROSITE documentation PDOC00434

Small cytokines (intercrine/chemokine) signatures

Many low-molecular weight factors secreted by cells including fibroblasts, macrophages and endothelial cells, in response to a variety of stimuli such as growth factors, interferons, viral transformation and bacterial products, are structurally related [1,2,3,E1]. Most members of this family of proteins seem to have mitogenic, chemotactic or inflammatory activities. These small cytokines are also called intercrines or chemokines. They are cationic proteins of 70 to 100 amino acid residues that share four conserved cysteine residues involved in two disulfide bonds, as shown in the following schematic representation:

                             +------------------------------------+
                             |                                    |
     xxxxxxxxxxxxxxxxxxxxxxCxCxxxxxxxxxxxxxxxxxxxxxxxCxxxxxxxxxxxxCxxxxx
                           |                         |
                           +-------------------------+

'C': conserved cysteine involved in a disulfide bond.

These proteins can be sorted into two groups based on the spacing of the two amino-terminal cysteines. In the first group, the two cysteines are separated by a single residue (C-x-C), while in the second group, they are adjacent (C-C).

The 'C-x-C' group is currently known to consist of the following proteins:

• Platelet factor 4 (PF4), a protein released from platelet α-granules as a complex with a proteoglycan molecule. PF4 neutralizes the anticoagulant effect of heparin because it binds more strongly to heparin than to the chondroitin-4-sulfate chains of the carrier molecule. PF4 is chemotactic for neutrophils and monocytes.
• Platelet basic protein (PBP), which is the precursor of two active peptides: connective-tissue activating peptide III (CTAP III) (also known as low- affinity platelet factor IV (LA-PF4)) and β-thromboglobulin. CTAP-III is a growth factor that stimulates a variety of specific metabolic and cellular activities.
• Interleukin-8 (IL-8), a monokine which is released from monocytes by an inflammatory response and which is selectively chemotactic for neutrophils. IL-8 is also known as Monocyte-Derived Neutrophil Chemotactic Factor (MDNCF), or as Neutrophil Activating Protein 1 (NAP-1).
• Melanoma growth stimulatory activity protein (MGSA), a growth factor with potent mitogenic activity. MGSA is also known as Neutrophil Activating Protein 3 (NAP-3) or as 'gro', as KC or N51 in mouse and as CICN in rat.
• Macrophage inflammatory protein 2 (MIP-2), an extremely potent chemotactic agent for polymorphonuclear leukocytes.
• Mouse Mig (m119), a γ-interferon induced protein that may be a cytokine affecting the growth, movement or activation state of cells that participate in immune and inflammatory response.
• Chicken 9E3 (or pCEF-4), a protein expressed constitutively in Rous Sarcoma virus (RSV) infected cells and which may be an autocrine factor that promotes the growth of fibroblasts.
• Pig alveolar macrophage chemotactic factors I and I (AMCF-I and -II).
• Pre-B cell growth stimulating factor (PBSF) (stromal cell-derived factor 1) (SDF-1).
• IP10, a γ-interferon induced protein which is chemotactic for monocytes and T lymphocytes.

The 'C-C' group is currently known to consist of the following proteins:

• Monocyte chemotactic protein 1 (MCP-1) [Also known as monocyte chemotactic and activating factor (MCAF); JE].
• Monocyte chemotactic protein 2 (MCP-2).
• Monocyte chemotactic protein 3 (MCP-3) [Also known as MARC; FIC].
• Monocyte chemotactic protein 4 (MCP-4) [Also known as NCC-1].
• Macrophage inflammatory protein 1 α (MIP-1-α) [Also known as SIS- α; TY-5; L2G25B; PAT 464.1; GOS19-1].
• Macrophage inflammatory protein 1 β (MIP-1-β) [Also known as SIS- γ; H400; ACT-2; PAT 744].
• Macrophage inflammatory protein 1 γ (MIP-1-γ) [Also known as macrophage inflammatory protein-related protein-2 (MRP2)].
• Macrophage inflammatory protein 3 α (MIP-3-α) [Also known as Liver and Activation-Regulated Chemokine (LARC)].
• Macrophage inflammatory protein 3 β (MIP-3-β) [Also known as EBI1- Ligand Chemokine (ELC)].
• Macrophage inflammatory protein 4 (MIP-4) [Also known as Pulmonary and Activation-Regulated Chemokine (PARC)].
• Macrophage inflammatory protein 5 (MIP-5) [Also known as HCC-2; NCC-3].
• LD78 β (also known as PAT 464.2 or GOS19-2).
• RANTES [Also known as SIS-delta].
• SIS-epsilon (p500).
• Thymus and activation-regulated chemokine (TARC).
• Eotaxin [Also known as eosinophil chemotactic protein].
• I-309 [Also known as TCA3].
• Human protein HCC-1/NCC-2.
• Human protein HCC-3.
• Mouse protein C10.

For each of the two groups of proteins, we have developed a signature pattern spanning the region that includes the four conserved cysteines.