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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 14

binds to the GTP-bound form of Rab27. The Slp and RBD • Rab-coupling protein (RCP) is also known as FIP1C
families also have two C-terminal C2 domains,which
enables these effectors to bind to phospholipids at the ClassII (have typical Ca 2 + -binding EF-hands)
plasma membrane and thus enables Rab27a to regulate
the secretory machinery at the vesicle docking step. The • FIP3, which is also known as Arfophilin and Eferin,
Slac2-a/Melanophilin and Slac2-c/MyRIP complexes link contributes to the role of Rab11 in trafficking and in-
Rab27a to molecular motors such as MyoVa (Module 4: sertion of membrane vesicles during formation of the
Figure myosin motor). The active Rab27.GTP carries out cleavage furrow responsible for cytokinesis (Module 9:
a number of functions: Figure cytokinesis).
• FIP4, which is also known as Arfophilin-2, functions
• One of the functions of RAB27A is to move melano-
somes along actin filaments in retinal pigment epithe- like FIP3 to regulate cytokinesis.
lium cells and in melanocytes. A defect in the transport
of melanocytes results in choroideraemia. In the case Mutations in FIP2/optineurin have been linked to
of melanogensis, Rab27A interacting with melanophilin some forms of glaucoma and amyotrophic lateral sclerosis
that then uses myosin Va to move melanosomes to the (ALS).
cell periphery of the melanocytes (Module 7: Figure
melanogenesis). Rac signalling mechanisms
• Another function of Rab27A is to regulate the secre- The Rac signalling pathway has an important role in ac-
tion of perforin- and granzyme-containing cytotoxic tivating a number of signalling pathways (Module 2: Fig-
granules at the immunological synapse that forms when ure Rac signalling). Like other G proteins, Rac functions
cytotoxic T lymphocytes (CTLs) and natural killer as a binary switch. It is inactive when bound to GDP,
(NK) cells interacts with their target cells, such as virus- but when this GDP is exchanged for GTP, the Rac/GTP
infected cells and tumour cells. Interaction of the T complex becomes active. External stimuli can activate this
cell receptor (TCR) with an antigen-presenting target switch using different guanine nucleotide exchange factors
cell induces the rapid polarization of the microtubule- (GEFs) such as T cell lymphoma invasion and metastasis
organizing center (MTOC), which orchestrates secre- (Tiam), Kalirin, Vav, SoS and P-Rex. Arf6, which particip-
tion of the cytotoxic granules at the immunological syn- ates in the Arf signalling pathway, stimulates the Rac GEF
apse. The Rab27 effector hMunc13-4 contributes to the called downstream of Crk-180 homologue (DOCK180).
maturation and exocytosis of the perforin-containing Kalirin functions in the Ephrin (Eph) receptor signalling
granules. Several inherited conditions, which lead to pathway, where it links the EphB receptor to Rac and actin
functional impairment of this cytotoxic pathway result assembly (Module 1: Figure Eph receptor signalling). The
from defects in either Rab27A or hMunc13-4. Muta- lipid second messenger PtdIns3,4,5P 3 , which is produced
tions in Rab27A have been linked to Griscelli syn- by the PtdIns 3-kinase signalling pathway, is particularly
drome type 2 (GS2), whereas mutations in hMunc13- effective in stimulating many of these GEFs.
4 cause familial hemophagocytic lymphohistiocytosis The activated Rac/GTP complex has a number of im-
type 3 (FHL3). portant actions:
• Insulin granules are tethered to the plasma membrane
using the effector Slp4-a/granuphilin-a to interact with A. Rac is responsible for mediating the action of the
both Rab27A and the SNARE protein syntaxin-1a.
PtdIns 3-kinase signalling pathway in stimulating the
• In glucagon-secreting α-cells in the pancreas, glucagon
NADPH oxidase to initiate the reactive oxygen species
granules are targeted to the plasma membrane by Slp2a.
(ROS) signalling pathway (Module 2: Figure plasma
membrane ROS formation).
Rab11-family interacting proteins (FIPs)
B. It stimulates the JNK (c-Jun N-terminal kinase) sig-
The Rab11-family interacting proteins (FIPs) serve as ef-
nalling pathway (Module 2: Figure JNK signalling).
fectors for a number of Rabs and ADP-ribosylation factors
C. It promotes actin stability by stimulating p21-activated
(Arfs). There are five members, which all have a Rab11-
kinase (PAK) to phosphorylate LIM kinase, which
binding domain (RBD) at the C-terminus and are divided
phosphorylates cofilin to inhibit its ability to cut actin.
into two classes:
D. It contributes to focal adhesion integrin signalling
Class I (have a phospholipid-binding C2 domain)
(Module 6: Figure integrin signalling).
• Rip11, which is also known as pp75 or FIP5, functions E. It promotes actin remodelling in several ways. It
in the transport of GLUT-4 vesicles to the cell surface stimulates PtdIns4P 5-kinase to increase the form-
when adipocytes are stimulated by insulin. ation of PtdIns4,5P 2 to control actin remodelling
• FIP2, which is also known as optineurin (OPTN), func- (Module 4: Figure actin remodelling). It also acts
tions to couple Rab 11 to the AMPA-containing syn- through insulin receptor substrate p53 (IRSp53),
aptic vesicles (Module 4: Figure myosin motor). Such which activates Wiskott-Aldrich syndrome pro-
trafficking events leading to receptor insertion are key tein (WASP) to co-ordinate the activity of the
components in the relationship between Ca 2 + and syn- actin-related protein 2/3 complex (Arp2/3 complex)
aptic plasticity during the process of learning (Module that initiates actin polymerization (Module 4: Figure
10: Figure Ca 2 + -induced synaptic plasticity). actin remodelling). Such a role is evident in neurons

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